List of publications on Pubmed: https://pubmed.ncbi.nlm.nih.gov/?term=khandelia+H&sort=date

  • [DOI] M. E. Sweet, X. Zhang, H. Erdjument-Bromage, V. Dubey, H. Khandelia, T. A. Neubert, B. P. Pedersen, and D. L. Stokes, “Serine phosphorylation regulates the p-type potassium pump KdpFABC,” eLife, vol. 9, 2020.
    [Bibtex]
    @article{Sweet2020,
    doi = {10.7554/elife.55480},
    url = {https://doi.org/10.7554/elife.55480},
    year = {2020},
    month = sep,
    publisher = {{eLife} Sciences Publications, Ltd},
    volume = {9},
    author = {Marie E Sweet and Xihui Zhang and Hediye Erdjument-Bromage and Vikas Dubey and Himanshu Khandelia and Thomas A Neubert and Bjorn P Pedersen and David L Stokes},
    title = {Serine phosphorylation regulates the P-type potassium pump {KdpFABC}},
    journal = {{eLife}}
    }
  • [DOI] C. D. Florentsen, A. Kamp-Sonne, G. Moreno-Pescador, W. Pezeshkian, A. A. H. Zanjani, H. Khandelia, J. Nylandsted, and P. M. Bendix, “Annexin a4 trimers are recruited by high membrane curvatures in giant plasma membrane vesicles,” Soft matter, 2020.
    [Bibtex]
    @article{Florentsen2020,
    doi = {10.1039/d0sm00241k},
    url = {https://doi.org/10.1039/d0sm00241k},
    year = {2020},
    publisher = {Royal Society of Chemistry ({RSC})},
    author = {Christoffer Dam Florentsen and Alexander Kamp-Sonne and Guillermo Moreno-Pescador and Weria Pezeshkian and Ali Asghar Hakami Zanjani and Himanshu Khandelia and Jesper Nylandsted and Poul Martin Bendix},
    title = {Annexin A4 trimers are recruited by high membrane curvatures in giant plasma membrane vesicles},
    journal = {Soft Matter}
    }
  • [DOI] S. F. Hedegaard, D. S. o, H. Khandelia, M. Cárdenas, and H. M. o, “Shuffled lipidation pattern and degree of lipidation determines the membrane interaction behavior of a linear cationic membrane-active peptide,” Journal of colloid and interface science, vol. 578, p. 584–597, 2020.
    [Bibtex]
    @article{Hedegaard2020,
    doi = {10.1016/j.jcis.2020.05.121},
    url = {https://doi.org/10.1016/j.jcis.2020.05.121},
    year = {2020},
    month = oct,
    publisher = {Elsevier {BV}},
    volume = {578},
    pages = {584--597},
    author = {Sofie Fogh Hedegaard and Dennis Skj{\o}th Bruhn and Himanshu Khandelia and Marit{\'{e}} C{\'{a}}rdenas and Hanne M{\o}rck Nielsen},
    title = {Shuffled lipidation pattern and degree of lipidation determines the membrane interaction behavior of a linear cationic membrane-active peptide},
    journal = {Journal of Colloid and Interface Science}
    }
  • [DOI] T. L. Toft-Bertelsen, B. R. Larsen, S. K. Christensen, H. Khandelia, H. S. Waagepetersen, and N. MacAulay, “Clearance of activity-evoked K+ transients and associated glia cell swelling occur independently of AQP4: A study with an isoform-selective AQP4 inhibitor,” GLIA.
    [Bibtex]
    @article{ ISI:000538294800001,
    Author = {Toft-Bertelsen, Trine Lisberg and Larsen, Brian Roland and Christensen,
    Sofie Kjellerup and Khandelia, Himanshu and Waagepetersen, Helle S. and
    MacAulay, Nanna},
    Title = {{Clearance of activity-evoked K+ transients and associated glia cell
    swelling occur independently of AQP4: A study with an isoform-selective
    AQP4 inhibitor}},
    Journal = {{GLIA}},
    Abstract = {{The mammalian brain consists of 80\% water, which is continuously
    shifted between different compartments and cellular structures by
    mechanisms that are, to a large extent, unresolved. Aquaporin 4 (AQP4)
    is abundantly expressed in glia and ependymal cells of the mammalian
    brain and has been proposed to act as a gatekeeper for brain water
    dynamics, predominantly based on studies utilizing AQP4-deficient mice.
    However, these mice have a range of secondary effects due to the gene
    deletion. An efficient and selective AQP4 inhibitor has thus been sorely
    needed to validate the results obtained in the AQP4(-/-) mice to
    quantify the contribution of AQP4 to brain fluid dynamics. In
    AQP4-expressing Xenopus laevis oocytes monitored by a high-resolution
    volume recording system, we here demonstrate that the compound TGN-020
    is such a selective AQP4 inhibitor. TGN-020 targets the tested species
    of AQP4 with an IC50 of similar to 3.5 mu M, but displays no inhibitory
    effect on the other AQPs (AQP1-AQP9). With this tool, we employed rat
    hippocampal slices and ion-sensitive microelectrodes to determine the
    role of AQP4 in glia cell swelling following neuronal activity.
    TGN-020-mediated inhibition of AQP4 did not prevent stimulus-induced
    extracellular space shrinkage, nor did it slow clearance of the
    activity-evoked K+ transient. These data, obtained with a verified
    isoform-selective AQP4 inhibitor, indicate that AQP4 is not required for
    the astrocytic contribution to the K+ clearance or the associated
    extracellular space shrinkage.}},
    DOI = {{10.1002/glia.23851}},
    Early Access Date = {{JUN 2020}},
    ISSN = {{0894-1491}},
    EISSN = {{1098-1136}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Waagepetersen, Helle/0000-0003-4583-8379
    Christensen, Sofie Kjellerup/0000-0003-2375-254X
    MacAulay, Nanna/0000-0002-7800-6600}},
    Unique-ID = {{ISI:000538294800001}},
    }
  • [DOI] B. Bozorg, M. A. Lomholt, and H. Khandelia, “Thermodynamic Investigation of the Mechanism of Heat Production During Membrane Depolarization,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. {124}, iss. {14}, p. {2815-2822}, {2020}.
    [Bibtex]
    @article{ ISI:000526869700009,
    Author = {Bozorg, Behruz and Lomholt, Michael Andersen and Khandelia, Himanshu},
    Title = {{Thermodynamic Investigation of the Mechanism of Heat Production During
    Membrane Depolarization}},
    Journal = {{JOURNAL OF PHYSICAL CHEMISTRY B}},
    Year = {{2020}},
    Volume = {{124}},
    Number = {{14}},
    Pages = {{2815-2822}},
    Month = {{APR 9}},
    Abstract = {{When an action potential passes through a neuron, heat is first produced
    and then reabsorbed by the neuronal membrane, resulting in a small
    measurable temperature spike. Here, we describe the thermodynamics and
    molecular features of the heat production using a coarse-grained
    molecular dynamics approach. We study a simple unicomponent lipid
    bilayer membrane surrounded by physiological salt solution with and
    without an external electric field, which represents an imbalanced
    charge across the membrane. We show that the temperature increases
    significantly upon removal of the electric field under constant pressure
    conditions. The potential energy converted to heat is initially stored
    mainly in the imbalanced ion distribution across the membrane and the
    elastic energy of the membrane has only a minor role to play. We
    demonstrate that the mechanism of heat production involves interaction
    between ions as well as lipid headgroup dipoles while the interactions
    between polar water molecules and lipid headgroup dipoles absorbs a
    considerable portion of such produced heat upon removal of the electric
    field. Our data provide novel thermodynamic insights into the molecular
    processes governing membrane reorganization upon discharging of lipid
    membranes and insight into energy metabolism in nerves.}},
    DOI = {{10.1021/acs.jpcb.9b11456}},
    ISSN = {{1520-6106}},
    EISSN = {{1520-5207}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Lomholt, Michael/0000-0002-3698-0958}},
    Unique-ID = {{ISI:000526869700009}},
    }
  • [DOI] P. M. Bendix, A. C. Simonsen, C. Florentsen, S. C. Haeger, A. Mularski, A. H. Zanjani, G. Moreno-Pescador, M. B. Klenow, S. L. Sonder, H. M. Danielsen, M. Arastoo, A. S. Heitmann, M. P. Pandey, F. W. Lund, C. Dias, H. Khandelia, and J. Nylandsted, “Interdisciplinary Synergy to Reveal Mechanisms of Annexin-Mediated Plasma Membrane Shaping and Repair,” CELLS, vol. {9}, iss. {4}, {2020}.
    [Bibtex]
    @article{ ISI:000535559500240,
    Author = {Bendix, Poul Martin and Simonsen, Adam Cohen and Florentsen, Christoffer
    D. and Haeger, Swantje Christin and Mularski, Anna and Zanjani, Ali
    Asghar Hakami and Moreno-Pescador, Guillermo and Klenow, Martin Berg and
    Sonder, Stine Lauritzen and Danielsen, Helena M. and Arastoo, Mohammad
    Reza and Heitmann, Anne Sofie and Pandey, Mayank Prakash and Lund,
    Frederik Wendelboe and Dias, Catarina and Khandelia, Himanshu and
    Nylandsted, Jesper},
    Title = {{Interdisciplinary Synergy to Reveal Mechanisms of Annexin-Mediated
    Plasma Membrane Shaping and Repair}},
    Journal = {{CELLS}},
    Year = {{2020}},
    Volume = {{9}},
    Number = {{4}},
    Month = {{APR}},
    Abstract = {{The plasma membrane surrounds every single cell and essentially shapes
    cell life by separating the interior from the external environment.
    Thus, maintenance of cell membrane integrity is essential to prevent
    death caused by disruption of the plasma membrane. To counteract plasma
    membrane injuries, eukaryotic cells have developed efficient repair
    tools that depend on Ca2+- and phospholipid-binding annexin proteins.
    Upon membrane damage, annexin family members are activated by a Ca2+
    influx, enabling them to quickly bind at the damaged membrane and
    facilitate wound healing. Our recent studies, based on interdisciplinary
    research synergy across molecular cell biology, experimental membrane
    physics, and computational simulations show that annexins have
    additional biophysical functions in the repair response besides enabling
    membrane fusion. Annexins possess different membrane-shaping properties,
    allowing for a tailored response that involves rapid bending,
    constriction, and fusion of membrane edges for resealing. Moreover, some
    annexins have high affinity for highly curved membranes that appear at
    free edges near rupture sites, a property that might accelerate their
    recruitment for rapid repair. Here, we discuss the mechanisms of
    annexin-mediated membrane shaping and curvature sensing in the light of
    our interdisciplinary approach to study plasma membrane repair.}},
    DOI = {{10.3390/cells9041029}},
    Article-Number = {{1029}},
    EISSN = {{2073-4409}},
    ResearcherID-Numbers = {{Moreno Pecador, Guillermo Sergio/K-6532-2015
    }},
    ORCID-Numbers = {{Berg Klenow, Martin/0000-0002-2045-8583
    Simonsen, Adam Cohen/0000-0003-1937-8524
    Nylandsted, Jesper/0000-0001-6474-5093
    Lauritzen Sonder, Stine/0000-0001-5551-4461
    Moreno Pecador, Guillermo Sergio/0000-0001-6923-9923
    Hakami Zanjani, Ali Asghar/0000-0002-0206-9074
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000535559500240}},
    }
  • [DOI] S. Sasidharan, S. Pochinda, P. Elgaard-Jorgensen, S. Rajamani, H. Khandelia, and V. A. Raghunathan, “Interaction of the mononucleotide UMP with a fluid phospholipid bilayer,” SOFT MATTER, vol. {15}, iss. {40}, p. {8129-8136}, {2019}.
    [Bibtex]
    @article{ ISI:000490786800012,
    Author = {Sasidharan, Sreeja and Pochinda, Simon and Elgaard-Jorgensen, Paninnguaq
    Naja and Rajamani, Sudha and Khandelia, Himanshu and Raghunathan, V. A.},
    Title = {{Interaction of the mononucleotide UMP with a fluid phospholipid bilayer}},
    Journal = {{SOFT MATTER}},
    Year = {{2019}},
    Volume = {{15}},
    Number = {{40}},
    Pages = {{8129-8136}},
    Month = {{OCT 28}},
    Abstract = {{Interaction between mononucleotides and lipid membranes is believed to
    have played an important role in the origin of life on Earth. Studies on
    mononucleotide-lipid systems hitherto have focused on the influence of
    the lipid environment on the organization of the mononucleotide
    molecules, and the effect of the latter on the confining medium has not
    been investigated in detail. We have probed the interaction of the
    mononucleotide, uridine 5 `-monophosphate (UMP), and its disodium salt
    (UMPDSS) with fluid dimyristoylphosphatidylcholine (DMPC) membranes,
    using small-angle X-ray scattering (SAXS), cryogenic scanning electron
    microscopy (cryo-SEM) and computer simulations. UMP adsorbs and charges
    the lipid membrane, resulting in the formation of unilamellar vesicles
    in dilute solutions. Adsorption of UMP reduces the bilayer thickness of
    DMPC. UMPDSS has a much weaker effect on interbilayer interactions.
    These observations are in very good agreement with the results of an
    all-atom molecular dynamics simulation of these systems. In the presence
    of counterions, such as Na+, UMP forms small aggregates in water, which
    bind to the bilayer without significantly perturbing it. The phosphate
    moiety in the lipid headgroup is found to bind to the hydrogens from the
    sugar ring of UMP, while the choline group tends to bind to the two
    oxygens from the nucleotide base. These studies provide important
    insights into lipid-nucleotide interactions and the effect of the
    nucleotide on lipid membranes.}},
    DOI = {{10.1039/c9sm01257e}},
    ISSN = {{1744-683X}},
    EISSN = {{1744-6848}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000490786800012}},
    }
  • [DOI] K. Yamamoto, V. Dubey, K. Irie, H. Nakanishi, H. Khandelia, Y. Fujiyoshi, and K. Abe, “A single K+-binding site in the crystal structure of the gastric proton pump,” ELIFE, vol. {8}, {2019}.
    [Bibtex]
    @article{ ISI:000482563800001,
    Author = {Yamamoto, Kenta and Dubey, Vikas and Irie, Katsumasa and Nakanishi,
    Hanayo and Khandelia, Himanshu and Fujiyoshi, Yoshinori and Abe,
    Kazuhiro},
    Title = {{A single K+-binding site in the crystal structure of the gastric proton
    pump}},
    Journal = {{ELIFE}},
    Year = {{2019}},
    Volume = {{8}},
    Month = {{AUG 22}},
    Abstract = {{The gastric proton pump (H+, K+-ATPase), a P-type ATPase responsible for
    gastric acidification, mediates electro-neutral exchange of H+ and K+
    coupled with ATP hydrolysis, but with an as yet undetermined transport
    stoichiometry. Here we show crystal structures at a resolution of 2.5
    angstrom of the pump in the E2-P transition state, in which the
    counter-transporting cation is occluded. We found a single K+ bound to
    the cation-binding site of the H+, K+-ATPase, indicating an exchange of
    1H(+)/1K(+) per hydrolysis of one ATP molecule. This fulfills the energy
    requirement for the generation of a six pH unit gradient across the
    membrane. The structural basis of K+ recognition is resolved and
    supported by molecular dynamics simulations, establishing how the H+,
    K+-ATPase overcomes the energetic challenge to generate an H+ gradient
    of more than a million-fold-one of the highest cation gradients known in
    mammalian tissue-across the membrane.}},
    DOI = {{10.7554/eLife.47701}},
    Article-Number = {{e47701}},
    ISSN = {{2050-084X}},
    ResearcherID-Numbers = {{Irie, Katsumasa/D-7332-2013
    Abe, Kazuhiro/D-7662-2013}},
    ORCID-Numbers = {{Irie, Katsumasa/0000-0002-8178-1552
    Khandelia, Himanshu/0000-0001-9913-6394
    Abe, Kazuhiro/0000-0003-2681-5921}},
    Unique-ID = {{ISI:000482563800001}},
    }
  • [DOI] A. Garcia, S. Pochinda, P. N. Elgaard-Jorgensen, H. Khandelia, and R. J. Clarke, “Evidence for ATP Interaction with Phosphatidylcholine Bilayers,” LANGMUIR, vol. {35}, iss. {30}, p. {9944-9953}, {2019}.
    [Bibtex]
    @article{ ISI:000479019700035,
    Author = {Garcia, Alvaro and Pochinda, Simon and Elgaard-Jorgensen, Paninnguaq N.
    and Khandelia, Himanshu and Clarke, Ronald J.},
    Title = {{Evidence for ATP Interaction with Phosphatidylcholine Bilayers}},
    Journal = {{LANGMUIR}},
    Year = {{2019}},
    Volume = {{35}},
    Number = {{30}},
    Pages = {{9944-9953}},
    Month = {{JUL 30}},
    Abstract = {{ATP is a fundamental intracellular molecule and is thought to diffuse
    freely throughout the cytosol. Evidence obtained from nucleotide-sensing
    sarcolemmal ion channels and red blood cells, however, suggest that ATP
    is compartmentalized or buffered, especially beneath the sarcolemma, but
    no definitive mechanism for restricted diffusion or potential buffering
    system has been postulated. In this study, we provide evidence from
    alterations to membrane dipole potential, membrane conductance, changes
    in enthalpy of phospholipid phase transition, and from free energy
    calculations that ATP associates with phospholipid bilayers.
    Furthermore, all-atom molecular dynamics simulations show that ATP can
    form aggregates in the aqueous phase at high concentrations. ATP
    interaction with membranes provides a new model to understand the
    diffusion of ATP through the cell. Coupled with previous reports of
    diffusion restriction in the subsarcolemmal space, these findings
    support the existence of compartmentalized or buffered pools of ATP.}},
    DOI = {{10.1021/acs.langmuir.9b01240}},
    ISSN = {{0743-7463}},
    ResearcherID-Numbers = {{Elgaard-Jorgensen, Paninnguaq Naja/F-2863-2013
    Clarke, Ronald J/L-5259-2016
    Garcia, Alvaro/E-6573-2015
    }},
    ORCID-Numbers = {{Clarke, Ronald J/0000-0002-0950-8017
    Garcia, Alvaro/0000-0002-1159-4567
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000479019700035}},
    }
  • [DOI] D. Dube, N. Ahalawat, H. Khandelia, J. Mondal, and S. Sengupta, “On identifying collective displacements in apo-proteins that reveal eventual binding pathways,” PLOS COMPUTATIONAL BIOLOGY, vol. {15}, iss. {1}, {2019}.
    [Bibtex]
    @article{ ISI:000457372500022,
    Author = {Dube, Dheeraj and Ahalawat, Navjeet and Khandelia, Himanshu and Mondal,
    Jagannath and Sengupta, Surajit},
    Title = {{On identifying collective displacements in apo-proteins that reveal
    eventual binding pathways}},
    Journal = {{PLOS COMPUTATIONAL BIOLOGY}},
    Year = {{2019}},
    Volume = {{15}},
    Number = {{1}},
    Month = {{JAN}},
    Abstract = {{Binding of small molecules to proteins often involves large
    conformational changes in the latter, which open up pathways to the
    binding site. Observing and pinpointing these rare events in large
    scale, all-atom, computations of specific protein-ligand complexes, is
    expensive and to a great extent serendipitous. Further, relevant
    collective variables which characterise specific binding or un-binding
    scenarios are still difficult to identify despite the large body of work
    on the subject. Here, we show that possible primary and secondary
    binding pathways can be discovered from short simulations of the
    apo-protein without waiting for an actual binding event to occur. We use
    a projection formalism, introduced earlier to study deformation in
    solids, to analyse local atomic displacements into two mutually
    orthogonal subspaces-those which are ``affine{''} i.e. expressible as a
    homogeneous deformation of the native structure, and those which are
    not. The susceptibility to non-affine displacements among the various
    residues in the apo-protein is then shown to correlate with typical
    binding pathways and sites crucial for allosteric modifications. We
    validate our observation with all-atom computations of three proteins,
    T4-Lysozyme, Src kinase and Cytochrome P450.}},
    DOI = {{10.1371/journal.pcbi.1006665}},
    Article-Number = {{e1006665}},
    EISSN = {{1553-7358}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Ahalawat, Navjeet/0000-0002-9665-8709
    Sengupta, Surajit/0000-0002-3221-7437}},
    Unique-ID = {{ISI:000457372500022}},
    }
  • [DOI] P. Siani, H. Khandelia, M. Orsi, and L. G. Dias, “Parameterization of a coarse-grained model of cholesterol with point-dipole electrostatics,” JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, vol. {32}, iss. {11}, p. {1259-1271}, {2018}.
    [Bibtex]
    @article{ ISI:000451435200004,
    Author = {Siani, P. and Khandelia, H. and Orsi, M. and Dias, L. G.},
    Title = {{Parameterization of a coarse-grained model of cholesterol with
    point-dipole electrostatics}},
    Journal = {{JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN}},
    Year = {{2018}},
    Volume = {{32}},
    Number = {{11}},
    Pages = {{1259-1271}},
    Month = {{NOV}},
    Abstract = {{We present a new coarse-grained (CG) model of cholesterol (CHOL) for the
    electrostatic-based ELBA force field. A distinguishing feature of our
    CHOL model is that the electrostatics is modeled by an explicit point
    dipole which interacts through an ideal vacuum permittivity. The CHOL
    model parameters were optimized in a systematic fashion, reproducing the
    electrostatic and nonpolar partitioning free energies of CHOL in
    lipid/water mixtures predicted by full-detailed atomistic molecular
    dynamics simulations. The CHOL model has been validated by comparison to
    structural, dynamic and thermodynamic properties with experimental and
    atomistic simulation reference data. The simulation of binary
    DPPC/cholesterol mixtures covering the relevant biological content of
    CHOL in mammalian membranes is shown to correctly predict the main lipid
    behavior as observed experimentally.}},
    DOI = {{10.1007/s10822-018-0164-4}},
    ISSN = {{0920-654X}},
    EISSN = {{1573-4951}},
    ResearcherID-Numbers = {{Dias, Luis Gustavo/AAD-9897-2019
    Dias, Luis G/G-2594-2012
    SIANI, PAULO/F-1706-2018}},
    ORCID-Numbers = {{Dias, Luis Gustavo/0000-0002-6151-7391
    Dias, Luis G/0000-0002-6151-7391
    Khandelia, Himanshu/0000-0001-9913-6394
    SIANI, PAULO/0000-0002-1930-4579}},
    Unique-ID = {{ISI:000451435200004}},
    }
  • [DOI] V. Dubey, M. Han, W. Kopec, I. A. Solov’yov, K. Abe, and H. Khandelia, “K+ binding and proton redistribution in the E2P state of the H+, K+-ATPase,” SCIENTIFIC REPORTS, vol. {8}, {2018}.
    [Bibtex]
    @article{ ISI:000442606500019,
    Author = {Dubey, Vikas and Han, Minwoo and Kopec, Wojciech and Solov'yov, Ilia A.
    and Abe, Kazuhiro and Khandelia, Himanshu},
    Title = {{K+ binding and proton redistribution in the E2P state of the H+,
    K+-ATPase}},
    Journal = {{SCIENTIFIC REPORTS}},
    Year = {{2018}},
    Volume = {{8}},
    Month = {{AUG 24}},
    Abstract = {{The H+, K+-ATPase (HKA) uses ATP to pump protons into the gastric lumen
    against a million-fold proton concentration gradient while
    counter-transporting K+ from the lumen. The mechanism of release of a
    proton into a highly acidic stomach environment, and the subsequent
    binding of a K+ ion necessitates a network of protonable residues and
    dynamically changing protonation states in the cation binding pocket
    dominated by five acidic amino acid residues E343, E795, E820, D824, and
    D942. We perform molecular dynamics simulations of spontaneous K+
    binding to all possible protonation combinations of the acidic amino
    acids and carry out free energy calculations to determine the optimal
    protonation state of the luminal-open E2P state of the pump which is
    ready to bind luminal K+. A dynamic pK(a) correlation analysis reveals
    the likelihood of proton transfer events within the cation binding
    pocket. In agreement with in-vitro measurements, we find that E795 is
    likely to be protonated, and that E820 is at the center of the proton
    transfer network in the luminal-open E2P state. The acidic residues D942
    and D824 are likely to remain protonated, and the proton redistribution
    occurs predominantly amongst the glutamate residues exposed to the
    lumen. The analysis also shows that a lower number of K+ ions bind at
    lower pH, modeled by a higher number of protons in the cation binding
    pocket, in agreement with the `transport stoichiometry variation'
    hypothesis.}},
    DOI = {{10.1038/s41598-018-30885-w}},
    Article-Number = {{12732}},
    ISSN = {{2045-2322}},
    ResearcherID-Numbers = {{Dubey, Vikas/H-7890-2019
    Abe, Kazuhiro/D-7662-2013
    }},
    ORCID-Numbers = {{Dubey, Vikas/0000-0002-0920-5593
    Abe, Kazuhiro/0000-0003-2681-5921
    Solov'yov, Ilia/0000-0002-8626-145X
    Khandelia, Himanshu/0000-0001-9913-6394
    Kopec, Wojciech/0000-0001-8801-9563}},
    Unique-ID = {{ISI:000442606500019}},
    }
  • [DOI] K. C. Courtney, W. Pezeshkian, R. Raghupathy, C. Zhang, A. Darbyson, J. H. Ipsen, D. A. Ford, H. Khandelia, J. F. Presley, and X. Zha, “C24 Sphingolipids Govern the Transbilayer Asymmetry of Cholesterol and Lateral Organization of Model and Live-Cell Plasma Membranes,” CELL REPORTS, vol. {24}, iss. {4}, p. {1037-1049}, {2018}.
    [Bibtex]
    @article{ ISI:000439589900022,
    Author = {Courtney, K. C. and Pezeshkian, W. and Raghupathy, R. and Zhang, C. and
    Darbyson, A. and Ipsen, J. H. and Ford, D. A. and Khandelia, H. and
    Presley, J. F. and Zha, X.},
    Title = {{C24 Sphingolipids Govern the Transbilayer Asymmetry of Cholesterol and
    Lateral Organization of Model and Live-Cell Plasma Membranes}},
    Journal = {{CELL REPORTS}},
    Year = {{2018}},
    Volume = {{24}},
    Number = {{4}},
    Pages = {{1037-1049}},
    Month = {{JUL 24}},
    Abstract = {{Mammalian sphingolipids, primarily with C24 or C16 acyl chains, reside
    in the outer leaflet of the plasma membrane. Curiously, little is known
    how C24 sphingolipids impact cholesterol and membrane microdomains.
    Here, we present evidence that C24 sphingomyelin, when placed in the
    outer leaflet, suppresses microdomains in giant unilamellar vesicles and
    also suppresses submicron domains in the plasma membrane of HeLa cells.
    Free energy calculations suggested that cholesterol has a preference for
    the inner leaflet if C24 sphingomyelin is in the outer leaflet. We
    indeed observe that cholesterol enriches in the inner leaflet (80\%) if
    C24 sphingomyelin is in the outer leaflet. Similarly, cholesterol
    primarily resides in the cytoplasmic leaflet (80\%) in the plasma
    membrane of human erythrocytes where C24 sphingolipids are naturally
    abundant in the outer leaflet. We conclude that C24 sphingomyelin
    uniquely interacts with cholesterol and regulates the lateral
    organization in asymmetric membranes, potentially by generating
    cholesterol asymmetry.}},
    DOI = {{10.1016/j.celrep.2018.06.104}},
    ISSN = {{2211-1247}},
    ResearcherID-Numbers = {{Ipsen, John/X-3216-2019
    }},
    ORCID-Numbers = {{Courtney, Kevin/0000-0003-1315-4917
    Khandelia, Himanshu/0000-0001-9913-6394
    Ipsen, John/0000-0002-1268-6180}},
    Unique-ID = {{ISI:000439589900022}},
    }
  • [DOI] C. R. Wewer and H. Khandelia, “Different footprints of the Zika and dengue surface proteins on viral membranes,” SOFT MATTER, vol. {14}, iss. {27}, p. {5615-5621}, {2018}.
    [Bibtex]
    @article{ ISI:000438395700009,
    Author = {Wewer, Christian R. and Khandelia, Himanshu},
    Title = {{Different footprints of the Zika and dengue surface proteins on viral
    membranes}},
    Journal = {{SOFT MATTER}},
    Year = {{2018}},
    Volume = {{14}},
    Number = {{27}},
    Pages = {{5615-5621}},
    Month = {{JUL 21}},
    Abstract = {{The flavivirus Zika virus (ZV) became an international emergency within
    two years of its outbreak in the Americas. Dengue virus (DENV), which is
    also a flavivirus, causes significant clinical harm in equatorial
    regions. A common feature amongst flaviviruses like ZV and DENV is an
    icosahedral shell of exactly 180 copies of the envelope (E) and membrane
    (M) proteins anchored in a lipid membrane, which engulfs the viral RNA
    and capsid proteins. Host recognition by both ZV and DENV is linked to
    the presence of phosphatidylserine (PS) and phosphatidylethanolamine
    (PE) lipids in the viral lipidome. Glycosylation of Asn residues on the
    Zika E protein may be linked to ZV induced neuropathies. We carry out
    coarse grained molecular dynamics simulations of the E3M3 hexamer
    embedded in the ZV and DENV lipidomes, and we show that the proteins
    have a significantly different lipid footprint in the viral lipidome. PE
    lipids in DENV and PS lipids in ZV enrich near the protein hexamer. We
    attribute the difference to a higher number of cationic amino acids in
    the ZV M protein. We also show that the three glycosylation sites on ZV,
    but not on DENV, are conformationally variant. Our data shed new light
    on the lipid interactions, and thus the host recognition mechanisms of
    the two viruses, which may be molecular determinants of the neuropathies
    caused by the ZV.}},
    DOI = {{10.1039/c8sm00223a}},
    ISSN = {{1744-683X}},
    EISSN = {{1744-6848}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000438395700009}},
    }
  • [DOI] K. Nguyen, A. Garcia, M. Sani, D. Diaz, V. Dubey, D. Clayton, G. Dal Poggetto, F. Cornelius, R. J. Payne, F. Separovic, H. Khandelia, and R. J. Clarke, “Interaction of N-terminal peptide analogues of the Na+,K+-ATPase with membranes,” BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, vol. {1860}, iss. {6}, p. {1282-1291}, {2018}.
    [Bibtex]
    @article{ ISI:000432758400004,
    Author = {Khoa Nguyen and Garcia, Alvaro and Sani, Marc-Antoine and Diaz, Dil and
    Dubey, Vikas and Clayton, Daniel and Dal Poggetto, Giovanni and
    Cornelius, Flemming and Payne, Richard J. and Separovic, Frances and
    Khandelia, Himanshu and Clarke, Ronald J.},
    Title = {{Interaction of N-terminal peptide analogues of the Na+,K+-ATPase with
    membranes}},
    Journal = {{BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES}},
    Year = {{2018}},
    Volume = {{1860}},
    Number = {{6}},
    Pages = {{1282-1291}},
    Month = {{JUN}},
    Abstract = {{The Na+,K+-ATPase, which is present in the plasma membrane of all animal
    cells, plays a crucial role in maintaining the Na+ and K+
    electrochemical potential gradients across the membrane. Recent studies
    have suggested that the N-terminus of the protein's catalytic
    alpha-subunit is involved in an electrostatic interaction with the
    surrounding membrane, which controls the protein's conformational
    equilibrium. However, because the N-terminus could not yet be resolved
    in any X-ray crystal structures, little information about this
    interaction is so far available. In measurements utilising poly-L-lysine
    as a model of the protein's lysine-rich N-terminus and using lipid
    vesicles of defined composition, here we have identified the most likely
    origin of the interaction as one between positively charged lysine
    residues of the N-terminus and negatively charged headgroups of
    phospholipids (notably phosphatidylserine) in the surrounding membrane.
    Furthermore, to isolate which segments of the N-terminus could be
    involved in membrane binding, we chemically synthesized N-terminal
    fragments of various lengths. Based on a combination of results from
    RH421 UV/visible absorbance measurements and solid-state P-31 and H-2
    NMR using these N-terminal fragments as well as MD simulations it
    appears that the membrane interaction arises from lysine residues prior
    to the conserved LKKE motif of the N-terminus. The MD simulations
    indicate that the strength of the interaction varies significantly
    between different enzyme conformations.}},
    DOI = {{10.1016/j.bbamem.2018.03.002}},
    ISSN = {{0005-2736}},
    EISSN = {{1879-2642}},
    ResearcherID-Numbers = {{Cornelius, Flemming/C-1912-2019
    Clarke, Ronald J/L-5259-2016
    Dubey, Vikas/H-7890-2019
    Garcia, Alvaro/E-6573-2015
    Separovic, Frances/D-9698-2011
    }},
    ORCID-Numbers = {{Cornelius, Flemming/0000-0003-1566-0020
    Clarke, Ronald J/0000-0002-0950-8017
    Dubey, Vikas/0000-0002-0920-5593
    Garcia, Alvaro/0000-0002-1159-4567
    Separovic, Frances/0000-0002-6484-2763
    Sani, Marc-antoine/0000-0003-3284-2176
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000432758400004}},
    }
  • [DOI] K. Olesen, N. Awasthi, D. S. Bruhn, W. Pezeshkian, and H. Khandelia, “Faster Simulations with a 5 fs Time Step for Lipids in the CHARMM Force Field,” JOURNAL OF CHEMICAL THEORY AND COMPUTATION, vol. {14}, iss. {6}, p. {3342-3350}, {2018}.
    [Bibtex]
    @article{ ISI:000435416200047,
    Author = {Olesen, Karma and Awasthi, Neha and Bruhn, Dennis S. and Pezeshkian,
    Weria and Khandelia, Himanshu},
    Title = {{Faster Simulations with a 5 fs Time Step for Lipids in the CHARMM Force
    Field}},
    Journal = {{JOURNAL OF CHEMICAL THEORY AND COMPUTATION}},
    Year = {{2018}},
    Volume = {{14}},
    Number = {{6}},
    Pages = {{3342-3350}},
    Month = {{JUN}},
    Abstract = {{The performance of all-atom molecular dynamics simulations is limited by
    an integration time step of 2 fs, which is needed to resolve the fastest
    degrees of freedom in the system, namely, the vibration of bonds and
    angles involving hydrogen atoms. The virtual interaction sites (VIS)
    method replaces hydrogen atoms by massless virtual interaction sites to
    eliminate these degrees of freedom while keeping intact nonbonded
    interactions and the explicit treatment of hydrogen atoms. We have
    modified the existing VIS algorithm for most lipids in the popular
    CHARMM36 force field by increasing the hydrogen atom masses at regular
    intervals in the lipid acyl chains and obtained lipid properties and
    pore formation free energies in very good agreement with those
    calculated in simulations without VIS. Our modified VIS scheme enables a
    5 fs time step resulting in a significant performance gain for all-atom
    simulations of membranes. The method has the potential to make longer
    time and length scales accessible in all-atom simulations of
    membrane-protein complexes.}},
    DOI = {{10.1021/acs.jctc.8b00267}},
    ISSN = {{1549-9618}},
    EISSN = {{1549-9626}},
    ORCID-Numbers = {{Pezeshkian, Weria/0000-0001-5509-0996
    Bruhn, Dennis Skjoth/0000-0003-1362-4747
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000435416200047}},
    }
  • [DOI] L. J. Nabo, M. Modzel, K. Krishnan, D. F. Covey, H. Fujiwara, D. S. Ory, M. Szomek, H. Khandelia, D. Wustner, and J. Kongsted, “Structural design of intrinsically fluorescent oxysterols,” CHEMISTRY AND PHYSICS OF LIPIDS, vol. {212}, p. {26-34}, {2018}.
    [Bibtex]
    @article{ ISI:000436207600003,
    Author = {Nabo, Lina J. and Modzel, Maciej and Krishnan, Kathiresan and Covey,
    Douglas F. and Fujiwara, Hideji and Ory, Daniel S. and Szomek, Maria and
    Khandelia, Himanshu and Wustner, Daniel and Kongsted, Jacob},
    Title = {{Structural design of intrinsically fluorescent oxysterols}},
    Journal = {{CHEMISTRY AND PHYSICS OF LIPIDS}},
    Year = {{2018}},
    Volume = {{212}},
    Pages = {{26-34}},
    Month = {{MAY}},
    Abstract = {{Oxysterols are oxidized derivatives of cholesterol with many important
    biological functions. Trafficking of oxysterols in and between cells is
    not well studied, largely due to the lack of appropriate oxysterol
    analogs. Intrinsically fluorescent oxysterols present a new route
    towards direct observation of intracellular oxysterol trafficking by
    fluorescence microscopy. We characterize the fluorescence properties of
    the existing fluorescent 25-hydroxycholesterol analog
    25-hydroxycholestatrienol, and propose a new probe with an extended
    conjugated system. The location of both probes inside a membrane is
    analyzed and compared with that of 25-hydroxycholesterol using molecular
    dynamics simulations. The analogs' one- and two-photon absorption
    properties inside the membrane are evaluated using electronic structure
    calculations with polarizable embedding. Due to predicted keto enol
    tautomerisation of the new oxysterol analog, we also evaluate the keto
    form. Both analogs are found to be good probe candidates for
    25-hydroxycholesterol, provided that the new analog remains in the
    enol-form. Only the new analog with extended conjugated system shows
    significant two-photon absorption, which is strongly enhanced by the
    presence of the membrane.}},
    DOI = {{10.1016/j.chemphyslip.2017.12.005}},
    ISSN = {{0009-3084}},
    EISSN = {{1873-2941}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Wustner, Daniel/0000-0003-4995-9709
    Kongsted, Jacob/0000-0002-7725-2164}},
    Unique-ID = {{ISI:000436207600003}},
    }
  • [DOI] W. Pezeshkian, H. Khandelia, and D. Marsh, “Lipid Configurations from Molecular Dynamics Simulations,” BIOPHYSICAL JOURNAL, vol. {114}, iss. {8}, p. {1895-1907}, {2018}.
    [Bibtex]
    @article{ ISI:000432692800014,
    Author = {Pezeshkian, Weria and Khandelia, Himanshu and Marsh, Derek},
    Title = {{Lipid Configurations from Molecular Dynamics Simulations}},
    Journal = {{BIOPHYSICAL JOURNAL}},
    Year = {{2018}},
    Volume = {{114}},
    Number = {{8}},
    Pages = {{1895-1907}},
    Month = {{APR 24}},
    Abstract = {{The extent to which current force fields faithfully reproduce
    conformational properties of lipids in bilayer membranes, and whether
    these reflect the structural principles established for phospholipids in
    bilayer crystals, are central to biomembrane simulations. We determine
    the distribution of dihedral angles in palmitoyl-oleoyl
    phosphatidylcholine from molecular dynamics simulations of hydrated
    fluid bilayer membranes. We compare results from the widely used lipid
    force field of Berger et al. with those from the most recent C36 release
    of the CHARMM force field for lipids. Only the CHARMM force field
    produces the chain inequivalence with sn-1 as leading chain that is
    characteristic of glycerolipid packing in fluid bilayers. The exposure
    and high partial charge of the backbone carbonyls in Berger lipids leads
    to artifactual binding of Na+ ions reported in the literature. Both
    force fields predict coupled, near-symmetrical distributions of
    headgroup dihedral angles, which is compatible with models of
    interconverting mirror-image conformations used originally to interpret
    NMR order parameters. The Berger force field produces rotamer
    populations that correspond to the headgroup conformation found in a
    phosphatidylcholine lipid bilayer crystal, whereas CHARMM36 rotamer
    populations are closer to the more relaxed crystal conformations of
    phosphatidylethanolamine and glycerophosphocholine. CHARMM36 alone
    predicts the correct relative signs of the timeaverage headgroup order
    parameters, and reasonably reproduces the full range of NMR data from
    the phosphate diester to the choline methyls. There is strong motivation
    to seek further experimental criteria for verifying predicted
    conformational distributions in the choline headgroup, including the
    P-31 chemical shift anisotropy and N-14 and CD3 NMR quadrupole
    splittings.}},
    DOI = {{10.1016/j.bpj.2018.02.016}},
    ISSN = {{0006-3495}},
    EISSN = {{1542-0086}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Pezeshkian, Weria/0000-0001-5509-0996}},
    Unique-ID = {{ISI:000432692800014}},
    }
  • [DOI] W. Pezeshkian, G. Chevrot, and H. Khandelia, “The role of caveolin-1 in lipid droplets and their biogenesis,” CHEMISTRY AND PHYSICS OF LIPIDS, vol. {211}, iss. {SI}, p. {93-99}, {2018}.
    [Bibtex]
    @article{ ISI:000428484800011,
    Author = {Pezeshkian, Weria and Chevrot, Guillaume and Khandelia, Himanshu},
    Title = {{The role of caveolin-1 in lipid droplets and their biogenesis}},
    Journal = {{CHEMISTRY AND PHYSICS OF LIPIDS}},
    Year = {{2018}},
    Volume = {{211}},
    Number = {{SI}},
    Pages = {{93-99}},
    Month = {{MAR}},
    Abstract = {{We address unresolved questions of the energetics and mechanism of lipid
    droplet (LD) biogenesis, and of the role of caveolins in the endoplasmic
    reticulum (ER) and in mature LDs. LDs are eukaryotic repositories of
    neutral lipids, which are believed to be synthesised in the ER. We
    investigate the effects of a curvature-inducing protein, caveolin-1, on
    the formation and structure of a spontaneously aggregated triolein (TO)
    lipid lens in a flat lipid bilayer using molecular dynamics (MD)
    simulations. A truncated form of caveolin-1 (Cav1) localises on the
    interface between the spontaneously formed TO aggregate and the bulk
    bilayer, and thins the bilayer at the edge of the aggregate, which may
    contribute to lowering the energy barrier for pinching off the aggregate
    from the host bilayer. Simulations of fully mature LDs do not
    conclusively establish the optimal localisation of Cav1 in LDs, but when
    Cav1 is in the LD core, the distribution of both neutral lipids in the
    LD core, and of phospholipids on the engulfing monolayer are altered
    significantly. Our simulations provide an unprecedented molecular
    description of the distribution and dynamics of various lipid species in
    both mature LDs and in the nascent LD inside the bilayer.}},
    DOI = {{10.1016/j.chemphyslip.2017.11.010}},
    ISSN = {{0009-3084}},
    EISSN = {{1873-2941}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Pezeshkian, Weria/0000-0001-5509-0996}},
    Unique-ID = {{ISI:000428484800011}},
    }
  • [DOI] L. Tranebjaerg, N. Strenzke, S. Lindholm, N. D. Rendtorff, H. Poulsen, H. Khandelia, W. Kopec, T. B. J. Lyngbye, C. Hamel, C. Delettre, B. Bocquet, M. Bille, H. H. Owen, T. Bek, H. Jensen, K. Ostergaard, C. Moller, L. Luxon, L. Carr, L. Wilson, K. Rajput, T. Sirimanna, K. Harrop-Griffiths, S. Rahman, B. Vona, J. Doll, T. Haaf, O. Bartsch, H. Rosewich, T. Moser, and M. Bitner-Glindzicz, “The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management,” HUMAN GENETICS, vol. {137}, iss. {2}, p. {111-127}, {2018}.
    [Bibtex]
    @article{ ISI:000425104600001,
    Author = {Tranebjaerg, Lisbeth and Strenzke, Nicola and Lindholm, Sture and
    Rendtorff, Nanna D. and Poulsen, Hanne and Khandelia, Himanshu and
    Kopec, Wojciech and Lyngbye, Troels J. Brunnich and Hamel, Christian and
    Delettre, Cecile and Bocquet, Beatrice and Bille, Michael and Owen,
    Hanne H. and Bek, Toke and Jensen, Hanne and Ostergaard, Karen and
    Moller, Claes and Luxon, Linda and Carr, Lucinda and Wilson, Louise and
    Rajput, Kaukab and Sirimanna, Tony and Harrop-Griffiths, Katherine and
    Rahman, Shamima and Vona, Barbara and Doll, Julia and Haaf, Thomas and
    Bartsch, Oliver and Rosewich, Hendrik and Moser, Tobias and
    Bitner-Glindzicz, Maria},
    Title = {{The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in
    auditory neuropathy which has implications for management}},
    Journal = {{HUMAN GENETICS}},
    Year = {{2018}},
    Volume = {{137}},
    Number = {{2}},
    Pages = {{111-127}},
    Month = {{FEB}},
    Abstract = {{Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural
    hearing impairment (CAPOS) is a rare clinically distinct syndrome caused
    by a single dominant missense mutation, c.2452G > A, p.Glu818Lys, in
    ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase
    alpha 3. Allelic mutations cause the neurological diseases rapid
    dystonia Parkinsonism and alternating hemiplegia of childhood, disorders
    which do not encompass hearing or visual impairment. We present detailed
    clinical phenotypic information in 18 genetically confirmed patients
    from 11 families (10 previously unreported) from Denmark, Sweden, UK and
    Germany indicating a specific type of hearing impairment-auditory
    neuropathy (AN). All patients were clinically suspected of CAPOS and had
    hearing problems. In this retrospective analysis of audiological data,
    we show for the first time that cochlear outer hair cell activity was
    preserved as shown by the presence of otoacoustic emissions and cochlear
    microphonic potentials, but the auditory brainstem responses were
    grossly abnormal, likely reflecting neural dyssynchrony. Poor speech
    perception was observed, especially in noise, which was beyond the
    hearing level obtained in the pure tone audiograms in several of the
    patients presented here. Molecular modelling and in vitro
    electrophysiological studies of the specific CAPOS mutation were
    performed. Heterologous expression studies of alpha 3 with the
    p.Glu818Lys mutation affects sodium binding to, and release from, the
    sodium-specific site in the pump, the third ion-binding site. Molecular
    dynamics simulations confirm that the structure of the C-terminal region
    is affected. In conclusion, we demonstrate for the first time evidence
    for auditory neuropathy in CAPOS syndrome, which may reflect impaired
    propagation of electrical impulses along the spiral ganglion neurons.
    This has implications for diagnosis and patient management. Auditory
    neuropathy is difficult to treat with conventional hearing aids, but
    preliminary improvement in speech perception in some patients suggests
    that cochlear implantation may be effective in CAPOS patients.}},
    DOI = {{10.1007/s00439-017-1862-z}},
    ISSN = {{0340-6717}},
    EISSN = {{1432-1203}},
    ResearcherID-Numbers = {{Rahman, Shamima/C-5232-2008
    Moser, Tobias/L-5068-2014
    Delettre, Cecile/AAC-3096-2020
    Bocquet, Beatrice/AAY-8447-2020
    Vona, Barbara/H-7377-2019
    Rahman, Shamima/M-7904-2019
    }},
    ORCID-Numbers = {{Rahman, Shamima/0000-0003-2088-730X
    Moser, Tobias/0000-0001-7145-0533
    Delettre, Cecile/0000-0003-3269-2155
    Bocquet, Beatrice/0000-0002-6369-4818
    Vona, Barbara/0000-0002-6719-3447
    Kopec, Wojciech/0000-0001-8801-9563
    Bek, Toke/0000-0002-0409-2534
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000425104600001}},
    }
  • [DOI] B. A. Doosti, W. Pezeshkian, D. S. Bruhn, J. H. Ipsen, H. Khandelia, G. D. M. Jeffries, and T. Lobovidna, “Membrane Tubulation in Lipid Vesicles Triggered by the Local Application of Calcium Ions,” LANGMUIR, vol. {33}, iss. {41}, p. {11010-11017}, {2017}.
    [Bibtex]
    @article{ ISI:000413392400026,
    Author = {Doosti, Baharan Ali and Pezeshkian, Weria and Bruhn, Dennis S. and
    Ipsen, John H. and Khandelia, Himanshu and Jeffries, Gavin D. M. and
    Lobovidna, Tatsiana},
    Title = {{Membrane Tubulation in Lipid Vesicles Triggered by the Local Application
    of Calcium Ions}},
    Journal = {{LANGMUIR}},
    Year = {{2017}},
    Volume = {{33}},
    Number = {{41}},
    Pages = {{11010-11017}},
    Month = {{OCT 17}},
    Abstract = {{Experimental and theoretical studies on ion-lipid interactions predict
    that binding of calcium ions to cell membranes leads to macroscopic
    mechanical effects and membrane remodeling. Herein, we provide
    experimental evidence that a point source of Ca2+ acting upon a
    negatively charged membrane generates spontaneous curvature and triggers
    the formation of tubular protrusions that point away from the ion
    source. This behavior is rationalized by strong binding of the divalent
    cations to the surface of the charged bilayer, which effectively
    neutralizes the surface charge density of outer leaflet of the bilayer.
    The mismatch in the surface charge density of the two leaflets leads to
    nonzero spontaneous curvature. We probe this mismatch through the use of
    molecular dynamics simulations and validate that calcium ion binding to
    a lipid membrane is sufficient to generate inward spontaneous curvature,
    bending the membrane. Additionally, we demonstrate that the formed
    tubular protrusions can be translated along the vesicle surface in a
    controlled manner by repositioning the site of localized Ca2+ exposure.
    The findings demonstrate lipid membrane remodeling in response to local
    chemical gradients and offer potential insights into the cell membrane
    behavior under conditions of varying calcium ion concentrations.}},
    DOI = {{10.1021/acs.langmuir.7b01461}},
    ISSN = {{0743-7463}},
    ResearcherID-Numbers = {{Ipsen, John/X-3216-2019
    Jeffries, Gavin D. M./F-5135-2011
    }},
    ORCID-Numbers = {{Jeffries, Gavin D. M./0000-0001-5533-169X
    Khandelia, Himanshu/0000-0001-9913-6394
    Ipsen, John/0000-0002-1268-6180
    Pezeshkian, Weria/0000-0001-5509-0996
    Ali Doosti, Baharan/0000-0001-9149-0751
    Bruhn, Dennis Skjoth/0000-0003-1362-4747}},
    Unique-ID = {{ISI:000413392400026}},
    }
  • [DOI] E. Adams, T. Miyazaki, A. Hayaishi-Satoh, M. Han, M. Kusano, H. Khandelia, K. Saito, and R. Shin, “A novel role for methyl cysteinate, a cysteine derivative, in cesium accumulation in Arabidopsis thaliana,” SCIENTIFIC REPORTS, vol. {7}, {2017}.
    [Bibtex]
    @article{ ISI:000394748800001,
    Author = {Adams, Eri and Miyazaki, Takae and Hayaishi-Satoh, Aya and Han, Minwoo
    and Kusano, Miyako and Khandelia, Himanshu and Saito, Kazuki and Shin,
    Ryoung},
    Title = {{A novel role for methyl cysteinate, a cysteine derivative, in cesium
    accumulation in Arabidopsis thaliana}},
    Journal = {{SCIENTIFIC REPORTS}},
    Year = {{2017}},
    Volume = {{7}},
    Month = {{FEB 23}},
    Abstract = {{Phytoaccumulation is a technique to extract metals from soil utilising
    ability of plants. Cesium is a valuable metal while radioactive isotopes
    of cesium can be hazardous. In order to establish a more efficient
    phytoaccumulation system, small molecules which promote plants to
    accumulate cesium were investigated. Through chemical library screening,
    14 chemicals were isolated as `cesium accumulators' in Arabidopsis
    thaliana. Of those, methyl cysteinate, a derivative of cysteine, was
    found to function within the plant to accumulate externally supplemented
    cesium. Moreover, metabolite profiling demonstrated that cesium
    treatment increased cysteine levels in Arabidopsis. The cesium
    accumulation effect was not observed for other cysteine derivatives or
    amino acids on the cysteine metabolic pathway tested. Our results
    suggest that methyl cysteinate, potentially metabolised from cysteine,
    binds with cesium on the surface of the roots or inside plant cells and
    improve phytoaccumulation.}},
    DOI = {{10.1038/srep43170}},
    Article-Number = {{43170}},
    ISSN = {{2045-2322}},
    ResearcherID-Numbers = {{Adams, Eri/AAF-7866-2020
    Saito, Kazuki/D-2670-2009
    Adams, Eri R/C-7436-2017
    }},
    ORCID-Numbers = {{Saito, Kazuki/0000-0001-6310-5342
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000394748800001}},
    }
  • [DOI] Q. Jiang, A. Garcia, M. Han, F. Cornelius, H. Apell, H. Khandelia, and R. J. Clarke, “Electrostatic Stabilization Plays a Central Role in Autoinhibitory Regulation of the Na+,K+-ATPase,” BIOPHYSICAL JOURNAL, vol. {112}, iss. {2}, p. {288-299}, {2017}.
    [Bibtex]
    @article{ ISI:000392886300008,
    Author = {Jiang, Qiucen and Garcia, Alvaro and Han, Minwoo and Cornelius, Flemming
    and Apell, Hans-Juergen and Khandelia, Himanshu and Clarke, Ronald J.},
    Title = {{Electrostatic Stabilization Plays a Central Role in Autoinhibitory
    Regulation of the Na+,K+-ATPase}},
    Journal = {{BIOPHYSICAL JOURNAL}},
    Year = {{2017}},
    Volume = {{112}},
    Number = {{2}},
    Pages = {{288-299}},
    Month = {{JAN 24}},
    Abstract = {{The Na+,K+-ATPase is present in the plasma membrane of all animal cells.
    It plays a crucial role in maintaining the Na+ and K+ electrochemical
    potential gradients across the membrane, which are essential in numerous
    physiological processes, e.g., nerve, muscle, and kidney function. Its
    cellular activity must, therefore, be under tight metabolic control.
    Consideration of eosin fluorescence and stopped-flow kinetic data
    indicates that the enzyme's E2 conformation is stabilized by
    electrostatic interactions, most likely between the N-terminus of the
    protein's catalytic alpha-subunit and the adjacent membrane. The
    electrostatic interactions can be screened by increasing ionic strength,
    leading to a more evenly balanced equilibrium between the E1 and E2
    conformations. This represents an ideal situation for effective
    regulation of the Na+,K+-ATPase's enzymatic activity, because protein
    modifications, which perturb this equilibrium in either direction, can
    then easily lead to activation or inhibition. The effect of ionic
    strength on the E1 :E2 distribution and the enzyme's kinetics can be
    mathematically described by the Gouy-Chapman theory of the electrical
    double layer. Weakening of the electrostatic interactions and a shift
    toward El causes a significant increase in the rate of phosphorylation
    of the enzyme by ATP. Electrostatic stabilization of the Na+,K+-ATPase's
    E2 conformation, thus, could play an important role in regulating the
    enzyme's physiological catalytic turnover.}},
    DOI = {{10.1016/j.bpj.2016.12.008}},
    ISSN = {{0006-3495}},
    EISSN = {{1542-0086}},
    ResearcherID-Numbers = {{Clarke, Ronald J/L-5259-2016
    Cornelius, Flemming/C-1912-2019
    Garcia, Alvaro/E-6573-2015
    }},
    ORCID-Numbers = {{Clarke, Ronald J/0000-0002-0950-8017
    Cornelius, Flemming/0000-0003-1566-0020
    Garcia, Alvaro/0000-0002-1159-4567
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000392886300008}},
    }
  • [DOI] M. Han, W. Kopec, I. A. Solov’yov, and H. Khandelia, “Glutamate Water Gates in the Ion Binding Pocket of Na+ Bound Na+, K+-ATPase,” SCIENTIFIC REPORTS, vol. {7}, {2017}.
    [Bibtex]
    @article{ ISI:000392160700001,
    Author = {Han, Minwoo and Kopec, Wojciech and Solov'yov, Ilia A. and Khandelia,
    Himanshu},
    Title = {{Glutamate Water Gates in the Ion Binding Pocket of Na+ Bound Na+,
    K+-ATPase}},
    Journal = {{SCIENTIFIC REPORTS}},
    Year = {{2017}},
    Volume = {{7}},
    Month = {{JAN 13}},
    Abstract = {{The dynamically changing protonation states of the six acidic amino acid
    residues in the ion binding pocket of the Na+, K+ -ATPase (NKA) during
    the ion transport cycle are proposed to drive ion binding, release and
    possibly determine Na+ or K+ selectivity. We use molecular dynamics (MD)
    and density functional theory (DFT) simulations to determine the
    protonation scheme of the Na+ bound conformation of NKA. MD simulations
    of all possible protonation schemes show that the bound Na+ ions are
    most stably bound when three or four protons reside in the binding
    sites, and that Glu954 in site III is always protonated. Glutamic acid
    residues in the three binding sites act as water gates, and their
    deprotonation triggers water entry to the binding sites. From DFT
    calculations of Na+ binding energies, we conclude that three protons in
    the binding site are needed to effectively bind Na+ from water and four
    are needed to release them in the next step. Protonation of Asp926 in
    site III will induce Na+ release, and Glu327, Glu954 and Glu779 are all
    likely to be protonated in the Na+ bound occluded conformation. Our data
    provides key insights into the role of protons in the Na+ binding and
    release mechanism of NKA.}},
    DOI = {{10.1038/srep39829}},
    Article-Number = {{39829}},
    ISSN = {{2045-2322}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Solov'yov, Ilia/0000-0002-8626-145X}},
    Unique-ID = {{ISI:000392160700001}},
    }
  • [DOI] P. Siani, R. M. de Souza, L. G. Dias, R. Itri, and H. Khandelia, “An overview of molecular dynamics simulations of oxidized lipid systems, with a comparison of ELBA and MARTINI force fields for coarse grained lipid simulations,” BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, vol. {1858}, iss. {10, SI}, p. {2498-2511}, {2016}.
    [Bibtex]
    @article{ ISI:000382340100020,
    Author = {Siani, P. and de Souza, R. M. and Dias, L. G. and Itri, R. and
    Khandelia, H.},
    Title = {{An overview of molecular dynamics simulations of oxidized lipid systems,
    with a comparison of ELBA and MARTINI force fields for coarse grained
    lipid simulations}},
    Journal = {{BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES}},
    Year = {{2016}},
    Volume = {{1858}},
    Number = {{10, SI}},
    Pages = {{2498-2511}},
    Month = {{OCT}},
    Abstract = {{Biological membranes and model lipid systems containing high amounts of
    unsaturated lipids and sterols are subject to chemical and/or
    photo-induced lipid oxidation, which leads to the creation of exotic
    oxidized lipid products (OxPLs). OxPLs are known to have significant
    physiological impact in cellular systems and also affect physical
    properties of both biological and model lipid bilayers. In this paper we
    (i) provide a perspective on the existing literature on simulations of
    lipid bilayer systems containing oxidized lipid species as well as the
    main related experimental results, (ii) describe our new data of
    all-atom and coarse -grained simulations of hydroperoxidized lipid
    monolayer and bilayer systems and (iii) provide a comparison of the
    MARTINI and ELBA coarse grained force fields for lipid bilayer systems.
    We show that the better electrostatic treatment of interactions in ELBA
    is able to resolve previous conflicts between experiments and
    simulations. This article is part of a Special Issue entitled:
    Biosimulations edited by Ilpo Vattulainen and Tomasz Rog. (C) 2016
    Elsevier B.V. All rights reserved.}},
    DOI = {{10.1016/j.bbamem.2016.03.031}},
    ISSN = {{0005-2736}},
    EISSN = {{0006-3002}},
    ResearcherID-Numbers = {{Dias, Luis G/G-2594-2012
    SIANI, PAULO/F-1706-2018
    Dias, Luis Gustavo/AAD-9897-2019
    Itri, Rosangela/B-4312-2014
    Maglia de Souza, Rafael/G-2184-2016
    }},
    ORCID-Numbers = {{Dias, Luis G/0000-0002-6151-7391
    SIANI, PAULO/0000-0002-1930-4579
    Dias, Luis Gustavo/0000-0002-6151-7391
    Maglia de Souza, Rafael/0000-0001-6272-9233
    Khandelia, Himanshu/0000-0001-9913-6394
    Itri, Rosangela/0000-0001-9311-0804}},
    Unique-ID = {{ISI:000382340100020}},
    }
  • [DOI] D. S. Bruhn, M. A. Lomholt, and H. Khandelia, “Quantifying the Relationship between Curvature and Electric Potential in Lipid Bilayers,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. {120}, iss. {21}, p. {4812-4817}, {2016}.
    [Bibtex]
    @article{ ISI:000377238800007,
    Author = {Bruhn, Dennis S. and Lomholt, Michael A. and Khandelia, Himanshu},
    Title = {{Quantifying the Relationship between Curvature and Electric Potential in
    Lipid Bilayers}},
    Journal = {{JOURNAL OF PHYSICAL CHEMISTRY B}},
    Year = {{2016}},
    Volume = {{120}},
    Number = {{21}},
    Pages = {{4812-4817}},
    Month = {{JUN 2}},
    Abstract = {{Cellular membranes mediate vital cellular processes by being subject to
    curvature and transmembrane electrical potentials. Here we build upon
    the existing theory for flexoelectricity in liquid crystals to quantify
    the coupling between lipid bilayer curvature and membrane potentials.
    Using molecular dynamics simulations, we show that headgroup dipole
    moments, the lateral pressure profile across the bilayer, and
    spontaneous curvature all systematically change with increasing membrane
    potentials. In particular, there is a linear dependence between the
    bending moment (the product of bending rigidity and spontaneous
    curvature) and the applied membrane potentials. We show that
    biologically relevant membrane potentials can induce biologically
    relevant curvatures corresponding to radii of around 500 nm. The
    implications of flexoelectricity in lipid bilayers are thus likely to be
    of considerable consequence both in biology and in model lipid bilayer
    systems.}},
    DOI = {{10.1021/acs.jpcb.6b03439}},
    ISSN = {{1520-6106}},
    EISSN = {{1520-5207}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Bruhn, Dennis Skjoth/0000-0003-1362-4747
    Lomholt, Michael/0000-0002-3698-0958}},
    Unique-ID = {{ISI:000377238800007}},
    }
  • [DOI] F. Hilbers, W. Kopec, T. J. Isaksen, T. H. Holm, K. Lykke-Hartmann, P. Nissen, H. Khandelia, and H. Poulsen, “Tuning of the Na,K-ATPase by the beta subunit,” SCIENTIFIC REPORTS, vol. {6}, {2016}.
    [Bibtex]
    @article{ ISI:000369440800001,
    Author = {Hilbers, Florian and Kopec, Wojciech and Isaksen, Toke Jost and Holm,
    Thomas Hellesoe and Lykke-Hartmann, Karin and Nissen, Poul and
    Khandelia, Himanshu and Poulsen, Hanne},
    Title = {{Tuning of the Na,K-ATPase by the beta subunit}},
    Journal = {{SCIENTIFIC REPORTS}},
    Year = {{2016}},
    Volume = {{6}},
    Month = {{FEB 5}},
    Abstract = {{The vital gradients of Na+ and K+ across the plasma membrane of animal
    cells are maintained by the Na, K-ATPase, an alpha beta enzyme complex,
    whose a subunit carries out the ion transport and ATP hydrolysis. The
    specific roles of the beta subunit isoforms are less clear, though beta
    2 is essential for motor physiology in mammals. Here, we show that
    compared to beta 1 and beta 3, beta 2 stabilizes the Na+-occluded E1P
    state relative to the outward-open E2P state, and that the effect is
    mediated by its transmembrane domain. Molecular dynamics simulations
    further demonstrate that the tilt angle of the beta transmembrane helix
    correlates with its functional effect, suggesting that the relative
    orientation of beta modulates ion binding at the alpha subunit. beta 2
    is primarily expressed in granule neurons and glomeruli in the
    cerebellum, and we propose that its unique functional characteristics
    are important to respond appropriately to the cerebellar Na+ and K+
    gradients.}},
    DOI = {{10.1038/srep20442}},
    Article-Number = {{20442}},
    ISSN = {{2045-2322}},
    ORCID-Numbers = {{Lykke-Hartmann, Karin/0000-0002-6702-183X
    Khandelia, Himanshu/0000-0001-9913-6394
    Nissen, Poul/0000-0003-0948-6628}},
    Unique-ID = {{ISI:000369440800001}},
    }
  • [DOI] W. Pezeshkian, A. G. Hansen, L. Johannes, H. Khandelia, J. C. Shillcock, P. B. S. Kumar, and J. H. Ipsen, “Membrane invagination induced by Shiga toxin B-subunit: from molecular structure to tube formation,” SOFT MATTER, vol. {12}, iss. {23}, p. {5164-5171}, {2016}.
    [Bibtex]
    @article{ ISI:000378943700012,
    Author = {Pezeshkian, W. and Hansen, A. G. and Johannes, L. and Khandelia, H. and
    Shillcock, J. C. and Kumar, P. B. S. and Ipsen, J. H.},
    Title = {{Membrane invagination induced by Shiga toxin B-subunit: from molecular
    structure to tube formation}},
    Journal = {{SOFT MATTER}},
    Year = {{2016}},
    Volume = {{12}},
    Number = {{23}},
    Pages = {{5164-5171}},
    Abstract = {{The bacterial Shiga toxin is composed of an enzymatically active
    A-subunit, and a receptor-binding homopentameric B-subunit (STxB) that
    mediates intracellular toxin trafficking. Upon STxB-mediated binding to
    the glycolipid globotriaosylceramide (Gb(3)) at the plasma membrane of
    target cells, Shiga toxin is internalized by clathrin-dependent and
    independent endocytosis. The formation of tubular membrane invaginations
    is an essential step in the clathrin-independent STxB uptake process.
    However, the mechanism by which STxB induces these invaginations has
    remained unclear. Using a combination of all-atom molecular dynamics and
    Monte Carlo simulations we show that the molecular architecture of STxB
    enables the following sequence of events: the Gb(3) binding sites on
    STxB are arranged such that tight avidity-based binding results in a
    small increment of local curvature. Membrane-mediated clustering of
    several toxin molecules then creates a tubular membrane invagination
    that drives toxin entry into the cell. This mechanism requires: (1) a
    precise molecular architecture of the STxB binding sites; (2) a fluid
    bilayer in order for the tubular invagination to form. Although, STxB
    binding to the membrane requires specific interactions with Gb(3)
    lipids, our study points to a generic molecular design principle for
    clathrin-independent endocytosis of nanoparticles.}},
    DOI = {{10.1039/c6sm00464d}},
    ISSN = {{1744-683X}},
    EISSN = {{1744-6848}},
    ResearcherID-Numbers = {{Johannes, Ludger/W-8593-2019
    Shillcock, Julian/I-8215-2016
    Johannes, Ludger/M-9778-2017
    Ipsen, John/X-3216-2019
    }},
    ORCID-Numbers = {{Johannes, Ludger/0000-0002-2168-0004
    Shillcock, Julian/0000-0002-7885-735X
    Johannes, Ludger/0000-0002-2168-0004
    Pezeshkian, Weria/0000-0001-5509-0996
    Khandelia, Himanshu/0000-0001-9913-6394
    Ipsen, John/0000-0002-1268-6180}},
    Unique-ID = {{ISI:000378943700012}},
    }
  • [DOI] L. J. Nabo, N. H. List, S. Witzke, D. Wustner, H. Khandelia, and J. Kongsted, “Design of new fluorescent cholesterol and ergosterol analogs: Insights from theory,” BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, vol. {1848}, iss. {10, A}, p. {2188-2199}, {2015}.
    [Bibtex]
    @article{ ISI:000362153400027,
    Author = {Nabo, Lina J. and List, Nanna H. and Witzke, Sarah and Wustner, Daniel
    and Khandelia, Himanshu and Kongsted, Jacob},
    Title = {{Design of new fluorescent cholesterol and ergosterol analogs: Insights
    from theory}},
    Journal = {{BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES}},
    Year = {{2015}},
    Volume = {{1848}},
    Number = {{10, A}},
    Pages = {{2188-2199}},
    Month = {{OCT}},
    Abstract = {{Cholesterol (Chol) and ergosterol (Erg) are abundant and important
    sterols in the plasma membrane of mammalian and yeast cells,
    respectively. The effects of Chol and Erg on membrane properties, as
    well as their intracellular transport, can be studied with use of
    fluorescence probes mimicking both sterols as closely as possible. In
    the search for new and efficient Chol and Erg probes, we use a
    combination of theoretical methods to explore a series of analogs. The
    optical properties of the analogs (i.e. excitation energies, emission
    energies and oscillator strengths) are examined using time-dependent
    density functional theory (TDDFT) and their ability to mimic the effects
    of Chol and Erg on membranes is investigated with molecular dynamics
    (MD) simulations of each analog in a
    1-palmitoy1-2-oleoyl-phosphatidylcholine (POPC) bilayer. From the set of
    analogs we find two probes (3a and 3b) to display favorable electronic
    transition properties as well as strong condensing abilities. These
    findings can lead to the use of new efficient probes and aid in the
    understanding of the structural features of Chol and Erg that impart to
    them their unique effects on lipid membranes. (C) 2015 Elsevier B.V. All
    rights reserved.}},
    DOI = {{10.1016/j.bbamem.2015.04.018}},
    ISSN = {{0005-2736}},
    EISSN = {{1879-2642}},
    ResearcherID-Numbers = {{List, Nanna Holmgaard/L-4049-2016
    List, Nanna Holmgaard/B-7047-2017}},
    ORCID-Numbers = {{Kongsted, Jacob/0000-0002-7725-2164
    Khandelia, Himanshu/0000-0001-9913-6394
    Nabo, Lina Johanna/0000-0002-4416-4029
    Wustner, Daniel/0000-0003-4995-9709
    List, Nanna Holmgaard/0000-0002-0246-3995}},
    Unique-ID = {{ISI:000362153400027}},
    }
  • [DOI] A. Garcia, N. D. Eljack, M. Sani, F. Separovic, H. H. Rasmussen, W. Kopec, H. Khandelia, F. Cornelius, and R. J. Clarke, “Membrane accessibility of glutathione,” BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, vol. {1848}, iss. {10, A}, p. {2430-2436}, {2015}.
    [Bibtex]
    @article{ ISI:000362153400053,
    Author = {Garcia, Alvaro and Eljack, Nasma D. and Sani, Marc-Antoine and
    Separovic, Frances and Rasmussen, Helge H. and Kopec, Wojciech and
    Khandelia, Himanshu and Cornelius, Flemming and Clarke, Ronald J.},
    Title = {{Membrane accessibility of glutathione}},
    Journal = {{BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES}},
    Year = {{2015}},
    Volume = {{1848}},
    Number = {{10, A}},
    Pages = {{2430-2436}},
    Month = {{OCT}},
    Abstract = {{Regulation of the ion pumping activity of the Na+,K+-ATPase is crucial
    to the survival of animal cells. Recent evidence has suggested that the
    activity of the enzyme could be controlled by glutathionylation of
    cysteine residue 45 of the beta-subunit Crystal structures so far
    available indicate that this cysteine is in a transmembrane domain of
    the protein. Here we have analysed via fluorescence and NMR spectroscopy
    as well as molecular dynamics simulations whether glutathione is able to
    penetrate into the interior of a lipid membrane. No evidence for any
    penetration of glutathione into the membrane was found. Therefore, the
    most likely mechanism whereby the cysteine residue could become
    glutathionylated is via a loosening of the alpha-beta subunit
    association, creating a hydrophilic passageway between them to allow
    access of glutathione to the cysteine residue. By such a mechanism,
    glutathionylation of the protein would be expected to anchor the
    modified cysteine residue in a hydrophilic environment, inhibiting
    further motion of the beta-subunit during the enzyme's catalytic cycle
    and suppressing enzymatic activity, as has been experimentally observed.
    The results obtained, therefore, suggest a possible structural mechanism
    of how the Na+,K+-ATPase could be regulated by glutathione. (c) 2015
    Elsevier B.V. All rights reserved.}},
    DOI = {{10.1016/j.bbamem.2015.07.016}},
    ISSN = {{0005-2736}},
    EISSN = {{1879-2642}},
    ResearcherID-Numbers = {{Cornelius, Flemming/C-1912-2019
    Garcia, Alvaro/E-6573-2015
    Clarke, Ronald J/L-5259-2016
    Separovic, Frances/D-9698-2011
    }},
    ORCID-Numbers = {{Cornelius, Flemming/0000-0003-1566-0020
    Garcia, Alvaro/0000-0002-1159-4567
    Clarke, Ronald J/0000-0002-0950-8017
    Separovic, Frances/0000-0002-6484-2763
    Kopec, Wojciech/0000-0001-8801-9563
    Sani, Marc-antoine/0000-0003-3284-2176
    Rasmussen, Helge/0000-0003-2409-4083
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000362153400053}},
    }
  • [DOI] S. K. Sahoo, S. A. Shaikh, D. H. Sopariwala, N. C. Bal, D. S. Bruhn, W. Kopec, H. Khandelia, and M. Periasamy, “The N Terminus of Sarcolipin Plays an Important Role in Uncoupling Sarco-endoplasmic Reticulum Ca2+-ATPase (SERCA) ATP Hydrolysis from Ca2+ Transport,” JOURNAL OF BIOLOGICAL CHEMISTRY, vol. {290}, iss. {22}, p. {14057-14067}, {2015}.
    [Bibtex]
    @article{ ISI:000355313000035,
    Author = {Sahoo, Sanjaya K. and Shaikh, Sana A. and Sopariwala, Danesh H. and Bal,
    Naresh C. and Bruhn, Dennis Skjoth and Kopec, Wojciech and Khandelia,
    Himanshu and Periasamy, Muthu},
    Title = {{The N Terminus of Sarcolipin Plays an Important Role in Uncoupling
    Sarco-endoplasmic Reticulum Ca2+-ATPase (SERCA) ATP Hydrolysis from Ca2+
    Transport}},
    Journal = {{JOURNAL OF BIOLOGICAL CHEMISTRY}},
    Year = {{2015}},
    Volume = {{290}},
    Number = {{22}},
    Pages = {{14057-14067}},
    Month = {{MAY 29}},
    Abstract = {{The sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) is responsible for
    intracellular Ca2+ homeostasis. SERCA activity in muscle can be
    regulated by phospholamban (PLB), an affinity modulator, and sarcolipin
    (SLN), an uncoupler. Although PLB gets dislodged from Ca2+-bound SERCA,
    SLN continues to bind SERCA throughout its kinetic cycle and promotes
    uncoupling of Ca2+ transport from ATP hydrolysis. To determine the
    structural regions of SLN that mediate uncoupling of SERCA, we employed
    mutagenesis and generated chimeras of PLB and SLN. In this study we
    demonstrate that deletion of SLN N-terminal residues (2)ERSTQ leads to
    loss of the uncoupling function even though the truncated peptide can
    target and constitutively bind SERCA. Furthermore, molecular dynamics
    simulations of SLN and SERCA interaction showed a rearrangement of SERCA
    residues that is altered when the SLN N terminus is deleted.
    Interestingly, transfer of the PLB cytosolic domain to the SLN
    transmembrane (TM) and luminal tail causes the chimeric protein to lose
    SLN-like function. Further introduction of the PLB TM region into this
    chimera resulted in conversion to full PLB-like function. We also found
    that swapping PLB N and C termini with those from SLN caused the
    resulting chimera to acquire SLN-like function. Swapping the C terminus
    alone was not sufficient for this conversion. These results suggest that
    domains can be switched between SLN and PLB without losing the ability
    to regulate SERCA activity; however, the resulting chimeras acquire
    functions different from the parent molecules. Importantly, our studies
    highlight that the N termini of SLN and PLB influence their respective
    unique functions.}},
    DOI = {{10.1074/jbc.M115.636738}},
    EISSN = {{1083-351X}},
    ResearcherID-Numbers = {{Regan, Clinton/E-6250-2012
    }},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Bruhn, Dennis Skjoth/0000-0003-1362-4747}},
    Unique-ID = {{ISI:000355313000035}},
    }
  • [DOI] E. Adams, V. Chaban, H. Khandelia, and R. Shin, “Selective chemical binding enhances cesium tolerance in plants through inhibition of cesium uptake,” SCIENTIFIC REPORTS, vol. {5}, {2015}.
    [Bibtex]
    @article{ ISI:000350455200002,
    Author = {Adams, Eri and Chaban, Vitaly and Khandelia, Himanshu and Shin, Ryoung},
    Title = {{Selective chemical binding enhances cesium tolerance in plants through
    inhibition of cesium uptake}},
    Journal = {{SCIENTIFIC REPORTS}},
    Year = {{2015}},
    Volume = {{5}},
    Month = {{MAR 5}},
    Abstract = {{High concentrations of cesium (Cs+) inhibit plant growth but the
    detailed mechanisms of Cs+ uptake, transport and response in plants are
    not well known. In order to identify small molecules with a capacity to
    enhance plant tolerance to Cs+, chemical library screening was performed
    using Arabidopsis. Of 10,000 chemicals tested, five compounds were
    confirmed as Cs+ tolerance enhancers. Further investigation and quantum
    mechanical modelling revealed that one of these compounds reduced Cs+
    concentrations in plants and that the imidazole moiety of this compound
    bound specifically to Cs+. Analysis of the analogous compounds indicated
    that the structure of the identified compound is important for the
    effect to be conferred. Taken together, Cs+ tolerance enhancer isolated
    here renders plants tolerant to Cs+ by inhibiting Cs+ entry into roots
    via specific binding to the ion thus, for instance, providing a basis
    for phytostabilisation of radiocesium-contaminated farmland.}},
    DOI = {{10.1038/srep08842}},
    Article-Number = {{8842}},
    ISSN = {{2045-2322}},
    ResearcherID-Numbers = {{Adams, Eri/AAF-7866-2020
    Adams, Eri R/C-7436-2017
    Shin, Ryoung/N-4766-2014
    }},
    ORCID-Numbers = {{Shin, Ryoung/0000-0003-4486-2852
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000350455200002}},
    }
  • [DOI] Y. A. Mahmmoud, W. Kopec, and H. Khandelia, “K+ Congeners That Do Not Compromise Na+ Activation of the Na+, K+-ATPase HYDRATION OF THE ION BINDING CAVITY LIKELY CONTROLS ION SELECTIVITY,” JOURNAL OF BIOLOGICAL CHEMISTRY, vol. {290}, iss. {6}, p. {3720-3731}, {2015}.
    [Bibtex]
    @article{ ISI:000349456000043,
    Author = {Mahmmoud, Yasser A. and Kopec, Wojciech and Khandelia, Himanshu},
    Title = {{K+ Congeners That Do Not Compromise Na+ Activation of the Na+, K+-ATPase
    HYDRATION OF THE ION BINDING CAVITY LIKELY CONTROLS ION SELECTIVITY}},
    Journal = {{JOURNAL OF BIOLOGICAL CHEMISTRY}},
    Year = {{2015}},
    Volume = {{290}},
    Number = {{6}},
    Pages = {{3720-3731}},
    Month = {{FEB 6}},
    Abstract = {{The Na+, K+-ATPase is essential for ionic homeostasis in animal cells.
    The dephosphoenzyme contains Na+ selective inward facing sites, whereas
    the phosphoenzyme contains K+ selective outward facing sites. Under
    normal physiological conditions, K+ inhibits cytoplasmic Na+ activation
    of the enzyme. Acetamidinium (Acet(+)) and formamidinium (Form(+)) have
    been shown to permeate the pump through the outward facing sites. Here,
    we show that these cations, unlike K+, are unable to enter the inward
    facing sites in the dephosphorylated enzyme. Consistently, the organic
    cations exhibited little to no antagonism to cytoplasmic Na+ activation.
    Na+, K+-ATPase structures revealed a previously undescribed rotamer
    transition of the hydroxymethyl side chain of the absolutely conserved
    Thr(772) of the alpha-subunit. The side chain contributes its hydroxyl
    to Na+ in site I in the E-1 form and rotates to contribute its methyl
    group toward K+ in the E-2 form. Molecular dynamics simulations to the
    E-1 center dot AlF4-center dot ADP center dot 3Na(+) structure indicated
    that 1) bound organic cations differentially distorted the ion binding
    sites, 2) the hydroxymethyl of Thr(772) rotates to stabilize bound
    Form(+) through water molecules, and 3) the rotamer transition is
    mediated by water traffic into the ion binding cavity. Accordingly,
    dehydration induced by osmotic stress enhanced the interaction of the
    congeners with the outward facing sites and profoundly modified the
    organization of membrane domains of the alpha-subunit. These results
    assign a catalytic role for water in pump function, and shed light on a
    backbone-independent but a conformation-dependent switch between H-bond
    and dispersion contact as part of the catalytic mechanism of the Na+,
    K+-ATPase.}},
    DOI = {{10.1074/jbc.M114.577486}},
    ISSN = {{0021-9258}},
    EISSN = {{1083-351X}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000349456000043}},
    }
  • [DOI] N. Jonnavithula, H. Khandelia, P. Durga, and G. Ramachandran, “Role of wound instillation with bupivacaine through surgical drains for postoperative analgesia in modified radical mastectomy,” INDIAN JOURNAL OF ANAESTHESIA, vol. {59}, iss. {1}, p. {15-20}, {2015}.
    [Bibtex]
    @article{ ISI:000371567400005,
    Author = {Jonnavithula, Nirmala and Khandelia, Harsh and Durga, Padmaja and
    Ramachandran, Gopinath},
    Title = {{Role of wound instillation with bupivacaine through surgical drains for
    postoperative analgesia in modified radical mastectomy}},
    Journal = {{INDIAN JOURNAL OF ANAESTHESIA}},
    Year = {{2015}},
    Volume = {{59}},
    Number = {{1}},
    Pages = {{15-20}},
    Month = {{JAN}},
    Abstract = {{Background and Aims: Modified Radical Mastectomy (MRM) is the commonly
    used surgical procedure for operable breast cancer, which involves
    extensive tissue dissection. Therefore, wound instillation with local
    anaesthetic may provide better postoperative analgesia than infiltration
    along the line of incision. We hypothesised that instillation of
    bupivacaine through chest and axillary drains into the wound may provide
    postoperative analgesia. Methods: In this prospective randomised
    controlled study 60 patients aged 45-60 years were divided into three
    groups. All patients were administered general anaesthesia. At the end
    of the surgical procedure, axillary and chest wall drains were placed
    before closure. Group C was the control with no instillation; Group S
    received 40 ml normal saline, 20 ml through each drain; and Group B
    received 40 ml of 0.25\% bupivacaine and the drains were clamped for 10
    min. After extubation, pain score for both static and dynamic pain was
    evaluated using visual analog scale and then 4th hourly till 24 h.
    Rescue analgesia was injection tramadol, if the pain score exceeds 4.
    Statistical analysis was performed using SPSS version 13. Results: There
    was a significant difference in the cumulative analgesic requirement and
    the number of analgesic demands between the groups (P: 0.000). The mean
    duration of analgesia in the bupivacaine group was 14.6 h, 10.3 in the
    saline group and 4.3 h in the control group. Conclusion: Wound
    instillation with local anaesthetics is a simple and effective means of
    providing good analgesia without any major side-effects.}},
    DOI = {{10.4103/0019-5049.149443}},
    ISSN = {{0019-5049}},
    EISSN = {{0976-2817}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000371567400005}},
    }
  • [DOI] W. Pezeshkian, V. V. Chaban, L. Johannes, J. Shillcock, J. H. Ipsena, and H. Khandelia, “The effects of globotriaosylceramide tail saturation level on bilayer phases,” SOFT MATTER, vol. {11}, iss. {7}, p. {1352-1361}, {2015}.
    [Bibtex]
    @article{ ISI:000349557100013,
    Author = {Pezeshkian, Weria and Chaban, Vitaly V. and Johannes, Ludger and
    Shillcock, Julian and Ipsena, John H. and Khandelia, Himanshu},
    Title = {{The effects of globotriaosylceramide tail saturation level on bilayer
    phases}},
    Journal = {{SOFT MATTER}},
    Year = {{2015}},
    Volume = {{11}},
    Number = {{7}},
    Pages = {{1352-1361}},
    Abstract = {{Globotriaosylceramide (Gb(3)) is a glycosphingolipid present in the
    plasma membrane that is the natural receptor of the bacterial Shiga
    toxin. The unsaturation level of Gb(3) acyl chains has a drastic impact
    on lipid bilayer properties and phase behaviour, and on many
    Gb(3)-related cellular processes. For example: the Shiga toxin B subunit
    forms tubular invaginations in the presence of Gb(3) with an unsaturated
    acyl chain (U-Gb(3)), while in the presence of Gb(3) with a saturated
    acyl chain (S-Gb(3)) such invagination does not occur. We have used
    all-atom molecular dynamics simulations to investigate the effects of
    the Gb(3) concentration and its acyl chain saturation on the phase
    behaviour of a mixed bilayer of dioleoylphosphatidylcholine and Gb(3).
    The simulation results show that: (1) the Gb(3) acyl chains (longer
    tails) from one leaflet interdigitate into the opposing leaflet and lead
    to significant bilayer rigidification and immobilisation of the lipid
    tails. S-Gb(3) can form a highly ordered, relatively immobile phase
    which is resistant to bending while these changes for U-Gb(3) are not
    significant. (2) At low concentrations of Gb(3), U-Gb(3) and S-Gb(3)
    have a similar impact on the bilayer reminiscent of the effect of
    sphingomyelin lipids and (3) At higher Gb(3) concentrations, U-Gb(3)
    mixes better with dioleoylphosphatidylcholine than S-Gb(3). Our
    simulations also provide the first molecular level structural model of
    Gb(3) in membranes.}},
    DOI = {{10.1039/c4sm02456g}},
    ISSN = {{1744-683X}},
    EISSN = {{1744-6848}},
    ResearcherID-Numbers = {{Johannes, Ludger/W-8593-2019
    Johannes, Ludger/M-9778-2017
    Shillcock, Julian/I-8215-2016
    }},
    ORCID-Numbers = {{Johannes, Ludger/0000-0002-2168-0004
    Johannes, Ludger/0000-0002-2168-0004
    Shillcock, Julian/0000-0002-7885-735X
    Khandelia, Himanshu/0000-0001-9913-6394
    Ipsen, John/0000-0002-1268-6180
    Pezeshkian, Weria/0000-0001-5509-0996}},
    Unique-ID = {{ISI:000349557100013}},
    }
  • [DOI] B. Loubet, W. Kopec, and H. Khandelia, “Accelerating All-Atom MD Simulations of Lipids Using a Modified Virtual-Sites Technique,” JOURNAL OF CHEMICAL THEORY AND COMPUTATION, vol. {10}, iss. {12}, p. {5690-5695}, {2014}.
    [Bibtex]
    @article{ ISI:000346324000050,
    Author = {Loubet, Bastien and Kopec, Wojciech and Khandelia, Himanshu},
    Title = {{Accelerating All-Atom MD Simulations of Lipids Using a Modified
    Virtual-Sites Technique}},
    Journal = {{JOURNAL OF CHEMICAL THEORY AND COMPUTATION}},
    Year = {{2014}},
    Volume = {{10}},
    Number = {{12}},
    Pages = {{5690-5695}},
    Month = {{DEC}},
    Abstract = {{We present two new implementations of the virtual sites technique which
    completely suppresses the degrees of freedom of the hydrogen atoms in a
    lipid bilayer allowing for an increased time step of 5 fs in all-atom
    simulations of the CHARMM36 force field. One of our approaches uses the
    derivation of the virtual sites used in GROMACS while the other uses a
    new definition of the virtual sites of the CH2 groups. Our methods is
    tested on a DPPC (no unsaturated chain), a POPC (one unsaturated chain),
    and a DOPC (two unsaturated chains) lipid bilayers. We calculate various
    physical properties of the membrane of our simulations with and without
    virtual sites and explain the differences and similarity observed. The
    best agreements are obtained for the GROMACS original virtual sites on
    the DOPC bilayer where we get an area per lipid of 67.3 +/- 0.3
    angstrom(2) without virtual sites and 67.6 +/- 0.3 angstrom(2) with
    virtual sites. In conclusion the virtual-sites technique on lipid
    membranes is a powerful simulation tool, but it should be used with
    care. The procedure can be applied to other force fields and lipids in a
    straightforward manner.}},
    DOI = {{10.1021/ct500100f}},
    ISSN = {{1549-9618}},
    EISSN = {{1549-9626}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000346324000050}},
    }
  • [DOI] V. V. Chaban and H. Khandelia, “Distribution of Neutral Lipids in the Lipid Droplet Core,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. {118}, iss. {38}, p. {11145-11151}, {2014}.
    [Bibtex]
    @article{ ISI:000342396000013,
    Author = {Chaban, Vitaly V. and Khandelia, Himanshu},
    Title = {{Distribution of Neutral Lipids in the Lipid Droplet Core}},
    Journal = {{JOURNAL OF PHYSICAL CHEMISTRY B}},
    Year = {{2014}},
    Volume = {{118}},
    Number = {{38}},
    Pages = {{11145-11151}},
    Month = {{SEP 25}},
    Abstract = {{Cholesteryl esters (CEs) are a form of cholesterol (CHOL) storage in the
    living cells, as opposed to free CHOL. CEs are major constituents of low
    density lipoprotein particles. Therefore, CEs are implicated in
    provoking atherosclerosis. Arranged into cytoplasmic lipid droplets
    (LDs), CEs are stored intracellularly. They can also be transported
    extracellularly by means of lipoproteins. In this work, large-scale
    molecular dynamics (MD) simulations are used to characterize the
    molecular structure of LDs containing various fractions (10-50 mol \%)
    of cholesteryl oleate (CO) with respect to triolein (TO) fraction. The
    simulated LDs were covered by a phospholipid monolayer formed by a
    mixture of 1-palmitoyl-2-oleoylphosphatidylcholine, POPC (75 mol \%),
    and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine, POPE (25 mol
    \%), molecules. We report that most CO molecules are located within the
    hydrophobic core of LDs, whereas a small fraction (0.3-1.9 mol \%)
    penetrates the monolayer. The solubility of CO in the phospholipid
    monolayer is relatively small. Due to a good miscibility with TO
    molecules, CO forms a liquid phase inside LD at 333 K. There is
    long-range order in the liquid TO-CO droplet core up to 8 nm from the
    phospholipid interface, resulting from the structuring of hydrophilic
    groups. This structuring slowly decays in the direction toward the LD
    center of mass. No sorting of TO and CO is detected, irrespective of the
    molar fractions simulated. The distribution of CO within the LDs is
    significant in determining the rate of their hydrolysis by surface-bound
    enzyme lipases, and thus has a subsequent impact on the levels of CO in
    plasma and LDLs.}},
    DOI = {{10.1021/jp506693d}},
    ISSN = {{1520-6106}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000342396000013}},
    }
  • [DOI] V. V. Chaban and H. Khandelia, “Lipid Structure in Triolein Lipid Droplets,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. {118}, iss. {35}, p. {10335-10340}, {2014}.
    [Bibtex]
    @article{ ISI:000341337500002,
    Author = {Chaban, Vitaly V. and Khandelia, Himanshu},
    Title = {{Lipid Structure in Triolein Lipid Droplets}},
    Journal = {{JOURNAL OF PHYSICAL CHEMISTRY B}},
    Year = {{2014}},
    Volume = {{118}},
    Number = {{35}},
    Pages = {{10335-10340}},
    Month = {{SEP 4}},
    Abstract = {{Lipid droplets (LDs) are primary repositories of esterified fatty acids
    and sterols in animal cells. These organelles originate on the lumenal
    or cytoplasmic side of endoplasmic reticulum (ER) membrane and are
    released to the cytosol. In contrast to other intracellular organelles,
    LDs are composed of a mass of hydrophobic lipid esters coved by
    phospholipid monolayer. The small size and unique architecture of LDs
    makes it complicated to study LD structure by modern experimental
    methods. We discuss coarse-grained molecular dynamics (MD) simulations
    of LD formation in systems containing
    1-palrnitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC),
    1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), triolein
    (TO), cholesterol (CHOL), and water. We find that (1) there is more
    cholesterol in the LD core, than at the interface. (2) No
    crystallization occurs inside the LD core. (3) According to
    coarse-grained simulations, the presence of PE lipids at the interface
    has a little impact on distribution of components and on the overall LD
    structure. (4) The thickness of the lipid monolayer at the surface of
    the droplet is similar to the thickness of one leaflet of a bilayer.
    Computer simulations are shown to be a mighty tool to provide
    molecular-level insights, which are not available to the experimental
    techniques.}},
    DOI = {{10.1021/jp503223z}},
    ISSN = {{1520-6106}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000341337500002}},
    }
  • [DOI] V. V. Chaban, M. B. Nielsen, W. Kopec, and H. Khandelia, “Insights into the role of cyclic ladderane lipids in bacteria from computer simulations,” CHEMISTRY AND PHYSICS OF LIPIDS, vol. {181}, p. {76-82}, {2014}.
    [Bibtex]
    @article{ ISI:000337778200006,
    Author = {Chaban, Vitaly V. and Nielsen, Morten B. and Kopec, Wojciech and
    Khandelia, Himanshu},
    Title = {{Insights into the role of cyclic ladderane lipids in bacteria from
    computer simulations}},
    Journal = {{CHEMISTRY AND PHYSICS OF LIPIDS}},
    Year = {{2014}},
    Volume = {{181}},
    Pages = {{76-82}},
    Month = {{JUL}},
    Abstract = {{Ladderanes, which are multiple fused cyclobutane rings, are unique
    structures available only in nature. Anammox bacteria produce ladderane
    phospholipids during their life cycle, but the synthesis mechanism still
    remains a mystery. The function of ladderane lipids in the membrane is
    unclear as well. According to previous speculations, ladderane moieties
    of the bilayer might decrease permeability for certain molecules, which
    should not diffuse out of the compartment enclosed by the
    ladderane-containing membrane. We report the first atomistic-precision
    molecular dynamics simulations of bilayers containing ladderane lipids.
    The structural and thermodynamics differences among (1) pure ladderane
    containing bilayer, (2) POPC bilayer, and (3) their equimolar mixture
    are discussed. Potentials of mean force are reported for the
    translocation of a hydrazine molecule through all investigated bilayers.
    All bilayers offer a potential energy barrier to hydrazine. Contrary to
    expectations, the presence of the ladderane lipids somewhat lowers the
    barrier for translocation of hydrazine. We conclude that the presence of
    ladderane phospholipids in anammox bacteria does not serve as a barrier
    to hydrazine. It may serve as a barrier to larger and noxious
    intermediates in the anammox reaction, or, the true mission of ladderane
    lipids must be located in a different plane. (C) 2014 Elsevier Ireland
    Ltd. All rights reserved.}},
    DOI = {{10.1016/j.chemphyslip.2014.04.002}},
    ISSN = {{0009-3084}},
    EISSN = {{1873-2941}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000337778200006}},
    }
  • [DOI] W. Kopec, B. Loubet, H. Poulsen, and H. Khandelia, “Molecular Mechanism of Na+,K+-ATPase Malfunction in Mutations Characteristic of Adrenal Hypertension,” BIOCHEMISTRY, vol. {53}, iss. {4}, p. {746-754}, {2014}.
    [Bibtex]
    @article{ ISI:000331015400015,
    Author = {Kopec, Wojciech and Loubet, Bastien and Poulsen, Hanne and Khandelia,
    Himanshu},
    Title = {{Molecular Mechanism of Na+,K+-ATPase Malfunction in Mutations
    Characteristic of Adrenal Hypertension}},
    Journal = {{BIOCHEMISTRY}},
    Year = {{2014}},
    Volume = {{53}},
    Number = {{4}},
    Pages = {{746-754}},
    Month = {{FEB 4}},
    Abstract = {{Mutations within ion-transporting proteins may severely affect their
    ability to traffic ions properly and thus perturb the delicate balance
    of ion gradients. Somatic gain-of-function mutations of the
    Na+,K+-ATPase alpha 1-subunit have been found in aldosterone-producing
    adenomas that are among the causes of hypertension. We used molecular
    dynamics simulations to investigate the structural consequences of these
    mutations, namely, Leu97 substitution by Arg (L97R), Val325 substitution
    by Gly (V325G), deletion of residues 93-97 (Del93-97), and
    deletion-substitution of residues 953-956 by Ser (EETA956S), which shows
    inward leak currents under physiological conditions. The first three
    mutations affect the structural context of the key ion-binding residue
    Glu327 at binding site II, which leads to the loss of the ability to
    bind ions correctly and to occlude the pump. The mutated residue in L97R
    is more hydrated, which ultimately leads to the observed proton leak.
    V325G mimics the structural behavior of L97R; however, it does not
    promote the hydration of surrounding residues. In Del93-97, a broader
    opening is observed because of the rearrangement of the kinked
    transmembrane helix 1, M1, which may explain the sodium leak measured
    with the mutant. The last mutant, EETA956S, opens an additional water
    pathway near the C-terminus, affecting the III sodium-specific binding
    site The results are in excellent agreement with recent
    electrophysiology measurements and suggest how three mutations prevent
    the occlusion of the Na+,K+-ATPase, with the possibility of transforming
    the pump into a passive ion channel, whereas the fourth mutation
    provides insight into the sodium binding in the El state.}},
    DOI = {{10.1021/bi401425g}},
    ISSN = {{0006-2960}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000331015400015}},
    }
  • [DOI] W. Kopec and H. Khandelia, “Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations,” JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, vol. {28}, iss. {2}, p. {123-134}, {2014}.
    [Bibtex]
    @article{ ISI:000332876400006,
    Author = {Kopec, Wojciech and Khandelia, Himanshu},
    Title = {{Reinforcing the membrane-mediated mechanism of action of the
    anti-tuberculosis candidate drug thioridazine with molecular simulations}},
    Journal = {{JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN}},
    Year = {{2014}},
    Volume = {{28}},
    Number = {{2}},
    Pages = {{123-134}},
    Month = {{FEB}},
    Abstract = {{Thioridazine is a well-known dopamine-antagonist drug with a wide range
    of pharmacological properties ranging from neuroleptic to antimicrobial
    and even anticancer activity. Thioridazine is a critical component of a
    promising multi-drug therapy against M. tuberculosis. Amongst the
    various proposed mechanisms of action, the cell membrane-mediated one is
    peculiarly tempting due to the distinctive feature of phenothiazine drug
    family to accumulate in selected body tissues. In this study, we employ
    long-scale molecular dynamics simulations to investigate the
    interactions of three different concentrations of thioridazine with
    zwitterionic and negatively charged model lipid membranes. Thioridazine
    partitions into the interfacial region of membranes and modifies their
    structural and dynamic properties, however dissimilarly so at the
    highest membrane-occurring concentration, that appears to be obtainable
    only for the negatively charged bilayer. We show that the origin of such
    changes is the drug induced decrease of the interfacial tension, which
    ultimately leads to the significant membrane expansion. Our findings
    support the hypothesis that the phenothiazines therapeutic activity may
    arise from the drug-membrane interactions, and reinforce the wider,
    emerging view of action of many small, bioactive compounds.}},
    DOI = {{10.1007/s10822-014-9737-z}},
    ISSN = {{0920-654X}},
    EISSN = {{1573-4951}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000332876400006}},
    }
  • [DOI] H. Khandelia, B. Loubet, A. Olzynska, P. Jurkiewicz, and M. Hof, “Pairing of cholesterol with oxidized phospholipid species in lipid bilayers,” SOFT MATTER, vol. {10}, iss. {4}, p. {639-647}, {2014}.
    [Bibtex]
    @article{ ISI:000328954900013,
    Author = {Khandelia, Himanshu and Loubet, Bastien and Olzynska, Agnieszka and
    Jurkiewicz, Piotr and Hof, Martin},
    Title = {{Pairing of cholesterol with oxidized phospholipid species in lipid
    bilayers}},
    Journal = {{SOFT MATTER}},
    Year = {{2014}},
    Volume = {{10}},
    Number = {{4}},
    Pages = {{639-647}},
    Abstract = {{We claim that (1) cholesterol protects bilayers from disruption caused
    by lipid oxidation by sequestering conical shaped oxidized lipid species
    such as 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PZPC) away
    from phospholipid, because cholesterol and the oxidized lipid have
    complementary shapes and (2) mixtures of cholesterol and oxidized lipids
    can self-assemble into bilayers much like lysolipid-cholesterol
    mixtures. The evidence for bilayer protection comes from molecular
    dynamics (MD) simulations and dynamic light scattering (DLS)
    measurements. Unimodal size distributions of extruded vesicles (LUVETs)
    made up of a mixture of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)
    and PZPC containing high amounts of PZPC are only obtained when
    cholesterol is present in high concentrations. In simulations, bilayers
    containing high amounts of PZPC become porous, unless cholesterol is
    also present. The protective effect of cholesterol on oxidized lipids
    has been observed previously using electron paramagnetic resonance (EPR)
    and electron microscopy imaging of vesicles. The evidence for the
    pairing of cholesterol and PZPC comes mainly from correlated 2-D density
    and thickness plots from simulations, which show that these two
    molecules co-localize in bilayers. Further evidence that the two
    molecules can cohabitate comes from self-assembly simulations, where we
    show that cholesterol-oxidized lipid mixtures can form lamellar phases
    at specific concentrations, reminiscent of lysolipid-cholesterol
    mixtures. The additivity of the packing parameters of cholesterol and
    PZPC explains their cohabitation in a planar bilayer. Oxidized lipids
    are ubiquitously present in significant amounts in high- and low-density
    lipoprotein (HDL and LDL) particles, diseased tissues, and in model
    phospholipid mixtures containing polyunsaturated lipids. Therefore, our
    hypothesis has important consequences for cellular cholesterol
    trafficking; diseases related to oxidized lipids, and to biophysical
    studies of phase behaviour of cholesterol-containing phospholipid
    mixtures.}},
    DOI = {{10.1039/c3sm52310a}},
    ISSN = {{1744-683X}},
    EISSN = {{1744-6848}},
    ResearcherID-Numbers = {{Hof, Martin/F-5134-2014
    Olzynska, Agnieszka/F-5152-2014
    Jurkiewicz, Piotr/F-5142-2014
    }},
    ORCID-Numbers = {{Hof, Martin/0000-0003-2884-3037
    Jurkiewicz, Piotr/0000-0002-7823-8962
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000328954900013}},
    }
  • [DOI] B. Loubet, M. A. Lomholt, and H. Khandelia, “Tension moderation and fluctuation spectrum in simulated lipid membranes under an applied electric potential,” JOURNAL OF CHEMICAL PHYSICS, vol. {139}, iss. {16}, {2013}.
    [Bibtex]
    @article{ ISI:000326637500080,
    Author = {Loubet, Bastien and Lomholt, Michael Andersen and Khandelia, Himanshu},
    Title = {{Tension moderation and fluctuation spectrum in simulated lipid membranes
    under an applied electric potential}},
    Journal = {{JOURNAL OF CHEMICAL PHYSICS}},
    Year = {{2013}},
    Volume = {{139}},
    Number = {{16}},
    Month = {{OCT 28}},
    Abstract = {{We investigate the effect of an applied electric potential on the
    mechanics of a coarse grained POPC bilayer under tension. The size and
    duration of our simulations allow for a detailed and accurate study of
    the fluctuations. Effects on the fluctuation spectrum, tension, bending
    rigidity, and bilayer thickness are investigated in detail. In
    particular, the least square fitting technique is used to calculate the
    fluctuation spectra. The simulations confirm a recently proposed theory
    that the effect of an applied electric potential on the membrane will be
    moderated by the elastic properties of the membrane. In agreement with
    the theory, we find that the larger the initial tension the larger the
    effect of the electric potential. Application of the electric potential
    increases the amplitude of the long wavelength part of the spectrum and
    the bending rigidity is deduced from the short wavelength fluctuations.
    The effect of the applied electric potential on the bending rigidity is
    non-existent within error bars. However, when the membrane is stretched
    there is a point where the bending rigidity is lowered due to a decrease
    of the thickness of the membrane. All these effects should prove
    important for mechanosensitive channels and biomembrane mechanics in
    general. (C) 2013 AIP Publishing LLC.}},
    DOI = {{10.1063/1.4826462}},
    Article-Number = {{164902}},
    ISSN = {{0021-9606}},
    EISSN = {{1089-7690}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Lomholt, Michael/0000-0002-3698-0958}},
    Unique-ID = {{ISI:000326637500080}},
    }
  • [DOI] A. H. Hansen, K. T. Sorensen, R. Mathieu, A. Serer, L. Duelund, H. Khandelia, P. L. Hansen, and A. C. Simonsen, “Propofol modulates the lipid phase transition and localizes near the headgroup of membranes,” CHEMISTRY AND PHYSICS OF LIPIDS, vol. {175}, p. {84-91}, {2013}.
    [Bibtex]
    @article{ ISI:000328595700012,
    Author = {Hansen, Anders Hojgaard and Sorensen, Kristian Tolbol and Mathieu,
    Richard and Serer, Alois and Duelund, Lars and Khandelia, Himanshu and
    Hansen, Per Lyngs and Simonsen, Adam Cohen},
    Title = {{Propofol modulates the lipid phase transition and localizes near the
    headgroup of membranes}},
    Journal = {{CHEMISTRY AND PHYSICS OF LIPIDS}},
    Year = {{2013}},
    Volume = {{175}},
    Pages = {{84-91}},
    Month = {{OCT-NOV}},
    Abstract = {{The compound 2,6-diisopropylphenol (Propofol, PRF) is widely used for
    inducing general anesthesia, but the mechanism of PRF action remains
    relatively poorly understood at the molecular level. This work examines
    the possibility that a potential mode of action of PRF is to modulate
    the lipid order in target membranes. The effect on monolayers and
    bilayers of dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC) was probed
    using Langmuir monolayer isotherms, differential scanning calorimetry
    (DSC), isothermal titration calorimetry (ITC) and molecular dynamics
    (MD) simulations. Increasing amounts of PRF in a DPPC monolayer causes a
    decrease in isothermal compressibility modulus at the phase transition.
    A partition constant for PRF in DPPC liposomes on the order of K
    approximate to 1500 M-1 was found, and the partitioning was found to be
    enthalpy-driven above the melting temperature (T.). A decrease in T.
    with PRF content was found whereas the bilayer melting enthalpy Delta
    H-m remains almost constant. The last finding indicates that PRF
    incorporates into the membrane at a depth near the phosphatidylcholine
    headgroup, in agreement with our MD-simulations. The simulations also
    reveal that PRF partitions into the membrane on a timescale of 0.5 mu s
    and has a cholesterol-like ordering effect on DPPC in the fluid phase.
    The vertical location of the PRF binding site in a bacterial
    ligand-gated ion channel coincides with the location found in our
    MD-simulations. Our results suggest that multiple physicochemical
    mechanisms may determine anesthetic potency of PRF, including effects on
    proteins that are mediated through the bilayer. (C) 2013 Elsevier
    Ireland Ltd. All rights reserved.}},
    DOI = {{10.1016/j.chemphyslip.2013.08.002}},
    ISSN = {{0009-3084}},
    EISSN = {{1873-2941}},
    ResearcherID-Numbers = {{Sorensen, Kristian/I-2421-2014
    Hojgaard Hansen, Anders/G-9662-2018
    Duelund, Lars/AAC-7110-2019
    }},
    ORCID-Numbers = {{Sorensen, Kristian/0000-0002-2875-6112
    Hojgaard Hansen, Anders/0000-0002-2572-9354
    Duelund, Lars/0000-0002-3786-2822
    Simonsen, Adam Cohen/0000-0003-1937-8524
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000328595700012}},
    }
  • [DOI] A. Hermetter, W. Kopec, and H. Khandelia, “Conformations of double-headed, triple-tailed phospholipid oxidation lipid products in model membranes,” BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, vol. {1828}, iss. {8}, p. {1700-1706}, {2013}.
    [Bibtex]
    @article{ ISI:000320838500005,
    Author = {Hermetter, Albin and Kopec, Wojciech and Khandelia, Himanshu},
    Title = {{Conformations of double-headed, triple-tailed phospholipid oxidation
    lipid products in model membranes}},
    Journal = {{BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES}},
    Year = {{2013}},
    Volume = {{1828}},
    Number = {{8}},
    Pages = {{1700-1706}},
    Month = {{AUG}},
    Abstract = {{Products of phospholipid oxidation can produce lipids with a carbonyl
    moiety at the end of a shortened lipid acyl tail, such as
    1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC). The
    carbonyl tail of POVPC can covalently bond to the free tertiary amine of
    a phosphatidylethanolamine lipid in a Schiff base reaction to form a
    conjugate lipid (SCH) with two head groups, and three acyl tails. We
    investigate the conformations and properties of this unique class of
    adduct lipids using molecular dynamics simulations, and show that their
    insertion into lipid bilayers of POPC increases the average
    cross-sectional area per lipid and decreases bilayer thickness.
    Significant increase in acyl tail fluidity is only observed at 25\% SCH
    concentration. The SCH occupies a larger area per lipid than expected
    for a lipid with three acyl tails, owing to the interfacial location of
    the long spacer between the two head groups of the SCH. Schiff base
    formation of lipids can alter the concentration, homeostasis and
    localizations of phosphatidylserine and phosphatidylethanol lipids in
    membranes, and can therefore influence several membrane-associated
    processes including fusion and budding. The current work provides the
    first detailed structural model of this unique new class of lipids that
    may have important roles to play in modulating membrane properties and
    cell physiology. (C) 2013 Elsevier B.V. All rights reserved.}},
    DOI = {{10.1016/j.bbamem.2013.03.030}},
    ISSN = {{0005-2736}},
    EISSN = {{1879-2642}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000320838500005}},
    }
  • [DOI] W. Kopec, J. Telenius, and H. Khandelia, “Molecular dynamics simulations of the interactions of medicinal plant extracts and drugs with lipid bilayer membranes,” FEBS JOURNAL, vol. {280}, iss. {12}, p. {2785-2805}, {2013}.
    [Bibtex]
    @article{ ISI:000320037900007,
    Author = {Kopec, Wojciech and Telenius, Jelena and Khandelia, Himanshu},
    Title = {{Molecular dynamics simulations of the interactions of medicinal plant
    extracts and drugs with lipid bilayer membranes}},
    Journal = {{FEBS JOURNAL}},
    Year = {{2013}},
    Volume = {{280}},
    Number = {{12}},
    Pages = {{2785-2805}},
    Month = {{JUN}},
    Abstract = {{Several small drugs and medicinal plant extracts, such as the Indian
    spice extract curcumin, have a wide range of useful pharmacological
    properties that cannot be ascribed to binding to a single protein target
    alone. The lipid bilayer membrane is thought to mediate the effects of
    many such molecules directly via perturbation of the plasma membrane
    structure and dynamics, or indirectly by modulating transmembrane
    protein conformational equilibria. Furthermore, for bioavailability,
    drugs must interact with and eventually permeate the lipid bilayer
    barrier on the surface of cells. Biophysical studies of the interactions
    of drugs and plant extracts are therefore of interest. Molecular
    dynamics simulations, which can access time and length scales that are
    not simultaneously accessible by other experimental methods, are often
    used to obtain quantitative molecular and thermodynamic descriptions of
    these interactions, often with complementary biophysical measurements.
    This review considers recent molecular dynamics simulations of small
    drug-like molecules with membranes, and provides a biophysical
    description of possible routes of membrane-mediated pharmacological
    effects of drugs. The review is not exhaustive, and we focus on
    molecules containing aromatic ring-like structures to develop our
    hypotheses. We also show that some drugs and anesthetics may have an
    effect on the lipid bilayer analogous to that of cholesterol.}},
    DOI = {{10.1111/febs.12286}},
    ISSN = {{1742-464X}},
    EISSN = {{1742-4658}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Telenius, Jelena/0000-0003-4353-3854}},
    Unique-ID = {{ISI:000320037900007}},
    }
  • [DOI] V. V. Chaban, B. Verspeek, and H. Khandelia, “Novel Ultrathin Membranes Composed of Organic Ions,” JOURNAL OF PHYSICAL CHEMISTRY LETTERS, vol. {4}, iss. {7}, p. {1216-1220}, {2013}.
    [Bibtex]
    @article{ ISI:000317317500028,
    Author = {Chaban, Vitaly V. and Verspeek, Bram and Khandelia, Himanshu},
    Title = {{Novel Ultrathin Membranes Composed of Organic Ions}},
    Journal = {{JOURNAL OF PHYSICAL CHEMISTRY LETTERS}},
    Year = {{2013}},
    Volume = {{4}},
    Number = {{7}},
    Pages = {{1216-1220}},
    Month = {{APR 4}},
    Abstract = {{Until recently, construction of bilayers was an exclusive mission of
    nature. It requires careful choice of compounds, whose delicate
    interplay between head group attraction and chain repulsion engenders a
    truly unique balance over a narrow temperature range. We report the
    investigation of artificial bilayers composed of long-chained organic
    ions, such as dodecyltrimethylammonium (DMA(+)) and perfluorooctaonate
    (PFO-). Various ratios of DMA/PFO surfactants result in bilayers of
    different stability, thickness, area per molecule, and density profiles.
    In our quest for water filtration, we incorporated aquaporin protein
    into the DMA/PFO bilayer but did not observe sufficient stability of the
    system. We discuss further steps to utilize these surfactant bilayers as
    highly selective, salt-impermeable membranes.}},
    DOI = {{10.1021/jz400424f}},
    ISSN = {{1948-7185}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000317317500028}},
    }
  • [DOI] E. Conte, F. M. Megli, H. Khandelia, G. Jeschke, and E. Bordignon, “Lipid peroxidation and water penetration in lipid bilayers: A W-band EPR study,” BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, vol. {1828}, iss. {2}, p. {510-517}, {2013}.
    [Bibtex]
    @article{ ISI:000315004600038,
    Author = {Conte, Elena and Megli, Francesco Maria and Khandelia, Himanshu and
    Jeschke, Gunnar and Bordignon, Enrica},
    Title = {{Lipid peroxidation and water penetration in lipid bilayers: A W-band EPR
    study}},
    Journal = {{BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES}},
    Year = {{2013}},
    Volume = {{1828}},
    Number = {{2}},
    Pages = {{510-517}},
    Month = {{FEB}},
    Abstract = {{Lipid peroxidation plays a key role in the alteration of cell membrane's
    properties. Here we used as model systems multilamellar vesicles (MLVs)
    made of the first two products in the oxidative cascade of linoleoyl
    lecithin, namely
    1-palmitoyl-2-(13-hydroperoxy-9,11-octadecanedienoyl)-lecithin (HpPLPC)
    and 1-palmitoyl-2-(13-hydroxy-9,11-octadecanedienoyl)-lecithin (OHPLPC),
    exhibiting a hydroperoxide or a hydroxy group at position 13,
    respectively. The two oxidized lipids were used either pure or in a 1:1
    molar ratio mixture with untreated 1-palmitoyl-2-linoleoyl-lecithin
    (PLPC). The model membranes were doped with spin-labeled lipids to study
    bilayer alterations by electron paramagnetic resonance (EPR)
    spectroscopy. Two different spin-labeled lipids were used, bearing the
    doxyl ring at position (n) 5 or 16:
    gamma-palmitoyl-beta-(n-doxylstearoyl)-lecithin (n-DSPPC) and
    n-doxylstearic acid (n-DSA).
    Small changes in the acyl chain order in the sub-polar region and at the
    methyl-terminal induced by lipid peroxidation were detected by X-band
    EPR. Concomitantly, the polarity and proticity of the membrane bilayer
    in those regions were investigated at W band in frozen samples. Analysis
    of the g(xx) and A(zz) parameters revealed that OHPLPC, but mostly
    HpPLPC, induced a measurable increase in polarity and H-bonding
    propensity in the central region of the bilayer. Molecular dynamics
    simulation performed on 16-DSA in the PLPC-HpPLPC bilayer revealed that
    water molecules are statistically favored with respect to the
    hydroperoxide groups to interact with the nitroxide at the
    methyl-terminal, confirming that the H-bonds experimentally observed are
    due to increased water penetration in the bilayer. The EPR and MD data
    on model membranes demonstrate that cell membrane damage by oxidative
    stress cause alteration of water penetration in the bilayer. (C) 2012
    Elsevier B.V. All rights reserved.}},
    DOI = {{10.1016/j.bbamem.2012.09.026}},
    ISSN = {{0005-2736}},
    EISSN = {{1879-2642}},
    ResearcherID-Numbers = {{Conte, Elena/AAV-3153-2020
    }},
    ORCID-Numbers = {{Conte, Elena/0000-0001-8571-5125
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000315004600038}},
    }
  • [DOI] O. G. Mouritsen and H. Khandelia, “Molecular mechanism of the allosteric enhancement of the umami taste sensation,” FEBS JOURNAL, vol. {279}, iss. {17}, p. {3112-3120}, {2012}.
    [Bibtex]
    @article{ ISI:000307883100009,
    Author = {Mouritsen, Ole G. and Khandelia, Himanshu},
    Title = {{Molecular mechanism of the allosteric enhancement of the umami taste
    sensation}},
    Journal = {{FEBS JOURNAL}},
    Year = {{2012}},
    Volume = {{279}},
    Number = {{17}},
    Pages = {{3112-3120}},
    Month = {{SEP}},
    Abstract = {{The fifth taste quality, umami, arises from binding of glutamate to the
    umami receptor T1R1/T1R3. The umami taste is enhanced several-fold upon
    addition of free nucleotides such as guanosine-5'-monophosphate (GMP) to
    glutamate-containing food. GMP may operate via binding to the
    ligand-binding domain of the T1R1 part of the umami receptor at an
    allosteric site. Using molecular dynamics simulations, we show that GMP
    can stabilize the closed (active) state of T1R1 by binding to the outer
    vestibule of the so-called Venus flytrap domain of the receptor. The
    transition between the closed and open conformations was accessed in the
    simulations. Using principal component analysis, we show that the
    dynamics of the Venus flytrap domain along the hinge-bending motion that
    activates signaling is dampened significantly upon binding of glutamate,
    and further slows down upon binding of GMP at an allosteric site, thus
    suggesting a molecular mechanism of cooperativity between GMP and
    glutamate.}},
    DOI = {{10.1111/j.1742-4658.2012.08690.x}},
    ISSN = {{1742-464X}},
    EISSN = {{1742-4658}},
    ORCID-Numbers = {{Mouritsen, Ole G./0000-0002-4258-8960
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000307883100009}},
    }
  • [DOI] H. Poulsen, P. Nissen, O. G. Mouritsen, and H. Khandelia, “Protein Kinase A (PKA) Phosphorylation of Na+/K+-ATPase Opens Intracellular C-terminal Water Pathway Leading to Third Na+-binding site in Molecular Dynamics Simulations,” JOURNAL OF BIOLOGICAL CHEMISTRY, vol. {287}, iss. {19}, p. {15959-15965}, {2012}.
    [Bibtex]
    @article{ ISI:000304006300074,
    Author = {Poulsen, Hanne and Nissen, Poul and Mouritsen, Ole G. and Khandelia,
    Himanshu},
    Title = {{Protein Kinase A (PKA) Phosphorylation of Na+/K+-ATPase Opens
    Intracellular C-terminal Water Pathway Leading to Third Na+-binding site
    in Molecular Dynamics Simulations}},
    Journal = {{JOURNAL OF BIOLOGICAL CHEMISTRY}},
    Year = {{2012}},
    Volume = {{287}},
    Number = {{19}},
    Pages = {{15959-15965}},
    Month = {{MAY 4}},
    Abstract = {{Phosphorylation is one of the major mechanisms for posttranscriptional
    modification of proteins. The addition of a compact, negatively charged
    moiety to a protein can significantly change its function and
    localization by affecting its structure and interaction network. We have
    used all-atom Molecular Dynamics simulations to investigate the
    structural consequences of phosphorylating the Na+/K+-ATPase (NKA)
    residue Ser(936), which is the best characterized phosphorylation site
    in NKA, targeted in vivo by protein kinase A (PKA). The Molecular
    Dynamics simulations suggest that Ser(936) phosphorylation opens a
    C-terminal hydrated pathway leading to Asp(926), a transmembrane residue
    proposed to form part of the third sodium ion-binding site. Simulations
    of a S936E mutant form, for which only subtle effects are observed when
    expressed in Xenopus oocytes and studied with electrophysiology, does
    not mimic the effects of Ser(936) phosphorylation. The results establish
    a structural association of Ser(936) with the C terminus of NKA and
    indicate that phosphorylation of Ser(936) can modulate pumping activity
    by changing the accessibility to the ion-binding site.}},
    DOI = {{10.1074/jbc.M112.340406}},
    EISSN = {{1083-351X}},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Nissen, Poul/0000-0003-0948-6628
    Mouritsen, Ole G./0000-0002-4258-8960}},
    Unique-ID = {{ISI:000304006300074}},
    }
  • [DOI] H. Khandelia, S. Witzke, and O. G. Mouritsen, “Interaction of Salicylate and a Terpenoid Plant Extract with Model Membranes: Reconciling Experiments and Simulations,” BIOPHYSICAL JOURNAL, vol. {99}, iss. {12}, p. {3887-3894}, {2010}.
    [Bibtex]
    @article{ ISI:000285438900011,
    Author = {Khandelia, Himanshu and Witzke, Sarah and Mouritsen, Ole G.},
    Title = {{Interaction of Salicylate and a Terpenoid Plant Extract with Model
    Membranes: Reconciling Experiments and Simulations}},
    Journal = {{BIOPHYSICAL JOURNAL}},
    Year = {{2010}},
    Volume = {{99}},
    Number = {{12}},
    Pages = {{3887-3894}},
    Month = {{DEC 15}},
    Abstract = {{model lipid bilayer, and show that both molecules might have biological
    activity related to membrane thinning. Salicylic acid is a nonsteroidal
    antiinflammatory drug, some of the pharmacological properties of which
    arise from its interaction with the lipid bilayer component of the
    plasma membrane. Prior simulations show that salicylate orders
    zwitterionic lipid membranes. However, this is in conflict with Raman
    scattering and vesicle fluctuation analysis data, which suggest the
    opposite. We show using extensive molecular dynamics simulations,
    cumulatively >2.5 mu s, that salicylic acid indeed disorders membranes
    with concomitant membrane thinning and that the conflict arose because
    prior simulations suffered from artifacts related to the sodium-ion
    induced condensation of zwitterionic lipids modeled by the Berger force
    field. Perillic acid is a terpenoid plant extract that has antiinfective
    and anticancer properties, and is extensively used in eastern medicine.
    We found that perillic acid causes large-scale membrane thinning and
    could therefore exert its antimicrobial properties via a membrane-lytic
    mechanism reminiscent of antimicrobial peptides. Being more amphipathic,
    perillic acid is more potent in disrupting lipid headgroup packing, and
    significantly modifies headgroup dipole orientation. Like salicylate,
    the membrane thinning effect of perillic acid is masked by the presence
    of sodium ions. As an alternative to sodium cations, we advocate the
    straightforward solution of using larger countercations like potassium
    or tetra-methyl-ammonium that will maintain electroneutrality but not
    interact strongly with, and thus not condense, the lipid bilayer.}},
    DOI = {{10.1016/j.bpj.2010.11.009}},
    ISSN = {{0006-3495}},
    EISSN = {{1542-0086}},
    ORCID-Numbers = {{Mouritsen, Ole G./0000-0002-4258-8960
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000285438900011}},
    }
  • [DOI] S. Witzke, L. Duelund, J. Kongsted, M. Petersen, O. G. Mouritsen, and H. Khandelia, “Inclusion of Terpenoid Plant Extracts in Lipid Bilayers Investigated by Molecular Dynamics Simulations,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. {114}, iss. {48}, p. {15825-15831}, {2010}.
    [Bibtex]
    @article{ ISI:000284738800012,
    Author = {Witzke, Sarah and Duelund, Lars and Kongsted, Jacob and Petersen,
    Michael and Mouritsen, Ole G. and Khandelia, Himanshu},
    Title = {{Inclusion of Terpenoid Plant Extracts in Lipid Bilayers Investigated by
    Molecular Dynamics Simulations}},
    Journal = {{JOURNAL OF PHYSICAL CHEMISTRY B}},
    Year = {{2010}},
    Volume = {{114}},
    Number = {{48}},
    Pages = {{15825-15831}},
    Month = {{DEC 9}},
    Abstract = {{The plant Perilla frutescens is widely employed in Asian medicine The
    active components of Perilla include cyclic terpenes, which have a
    diverse range of antimicrobial, anticancer, sedative, and
    anti-inflammatory properties, hinting at a membrane-mediated mechanism
    of action We have used molecular dynamics (MD) simulations and
    isothermal titration calorimetry (ITC) to investigate the interaction of
    four terpenes with model lipid bilayers The ITC and MD data are mostly
    in accordance The terpenes partition into membranes, pack along the
    lipid tails, and alter bilayer structure and dynamics Three of the four
    molecules could cross the bilayer The carboxylate-group-containing
    terpene modifies headgroup repulsion and increases the area per lipid by
    more than 10\% in a manner reminiscent of membrane-thinning peptides and
    solvents such as DMSO Our results support the possibility that at least
    some medicinal properties of volatile Perilla extracts might arise from
    interactions with the lipid bilayer component of biological membranes}},
    DOI = {{10.1021/jp108675b}},
    ISSN = {{1520-6106}},
    ResearcherID-Numbers = {{Duelund, Lars/AAC-7110-2019
    }},
    ORCID-Numbers = {{Duelund, Lars/0000-0002-3786-2822
    Kongsted, Jacob/0000-0002-7725-2164
    Khandelia, Himanshu/0000-0001-9913-6394
    Petersen, Michael/0000-0002-0997-7657
    Mouritsen, Ole G./0000-0002-4258-8960}},
    Unique-ID = {{ISI:000284738800012}},
    }
  • [DOI] H. Khandelia, L. Duelund, K. I. Pakkanen, and J. H. Ipsen, “Triglyceride Blisters in Lipid Bilayers: Implications for Lipid Droplet Biogenesis and the Mobile Lipid Signal in Cancer Cell Membranes,” PLOS ONE, vol. {5}, iss. {9}, {2010}.
    [Bibtex]
    @article{ ISI:000282053100010,
    Author = {Khandelia, Himanshu and Duelund, Lars and Pakkanen, Kirsi I. and Ipsen,
    John H.},
    Title = {{Triglyceride Blisters in Lipid Bilayers: Implications for Lipid Droplet
    Biogenesis and the Mobile Lipid Signal in Cancer Cell Membranes}},
    Journal = {{PLOS ONE}},
    Year = {{2010}},
    Volume = {{5}},
    Number = {{9}},
    Month = {{SEP 22}},
    Abstract = {{Triglycerides have a limited solubility, around 3\%, in
    phosphatidylcholine lipid bilayers. Using millisecond-scale course
    grained molecular dynamics simulations, we show that the model lipid
    bilayer can accommodate a higher concentration of triolein (TO) than
    earlier anticipated, by sequestering triolein molecules to the bilayer
    center in the form of a disordered, isotropic, mobile neutral lipid
    aggregate, at least 17 nm in diameter, which forms spontaneously, and
    remains stable on at least the microsecond time scale. The results give
    credence to the hotly debated existence of mobile neutral lipid
    aggregates of unknown function present in malignant cells, and to the
    early biogenesis of lipid droplets accommodated between the two leaflets
    of the endoplasmic reticulum membrane. The TO aggregates give the
    bilayer a blister-like appearance, and will hinder the formation of
    multi-lamellar phases in model, and possibly living membranes. The
    blisters will result in anomalous membrane probe partitioning, which
    should be accounted for in the interpretation of probe-related
    measurements.}},
    DOI = {{10.1371/journal.pone.0012811}},
    Article-Number = {{e12811}},
    ISSN = {{1932-6203}},
    ResearcherID-Numbers = {{Ipsen, John/X-3216-2019
    Duelund, Lars/AAC-7110-2019
    }},
    ORCID-Numbers = {{Duelund, Lars/0000-0002-3786-2822
    Ipsen, John/0000-0002-1268-6180
    Khandelia, Himanshu/0000-0001-9913-6394
    Pakkanen, Kirsi/0000-0002-3215-6937}},
    Unique-ID = {{ISI:000282053100010}},
    }
  • [DOI] H. Poulsen, H. Khandelia, P. J. Morth, M. Bublitz, O. G. Mouritsen, J. Egebjerg, and P. Nissen, “Neurological disease mutations compromise a C-terminal ion pathway in the Na+/K+-ATPase,” NATURE, vol. {467}, iss. {7311}, p. {99-102}, {2010}.
    [Bibtex]
    @article{ ISI:000281461200043,
    Author = {Poulsen, Hanne and Khandelia, Himanshu and Morth, J. Preben and Bublitz,
    Maike and Mouritsen, Ole G. and Egebjerg, Jan and Nissen, Poul},
    Title = {{Neurological disease mutations compromise a C-terminal ion pathway in
    the Na+/K+-ATPase}},
    Journal = {{NATURE}},
    Year = {{2010}},
    Volume = {{467}},
    Number = {{7311}},
    Pages = {{99-102}},
    Month = {{SEP 2}},
    Abstract = {{The Na+/K+-ATPase pumps three sodium ions out of and two potassium ions
    into the cell for each ATP molecule that is split, thereby generating
    the chemical and electrical gradients across the plasma membrane that
    are essential in, for example, signalling, secondary transport and
    volume regulation in animal cells. Crystal structures of the
    potassium-bound form of the pump revealed an intimate docking of the
    alpha-subunit carboxy terminus at the transmembrane domain(1,2). Here we
    show that this element is a key regulator of a previously unrecognized
    ion pathway. Current models of P-type ATPases operate with a single ion
    conduit through the pump(3-5), but our data suggest an additional
    pathway in the Na+/K+-ATPase between the ion-binding sites and the
    cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter
    and stabilize site III when empty in the potassium-bound state, and when
    potassium is released the proton will also return to the cytoplasm, thus
    allowing an overall asymmetric stoichiometry of the transported ions.
    The C terminus controls the gate to the pathway. Its structure is
    crucial for pump function, as demonstrated by at least eight mutations
    in the region that cause severe neurological diseases(6,7). This novel
    model for ion transport by the Na+/K+-ATPase is established by
    electrophysiological studies of C-terminal mutations in familial
    hemiplegic migraine 2 (FHM2) and is further substantiated by molecular
    dynamics simulations. A similar ion regulation is likely to apply to the
    H+/K+-ATPase and the Ca2+-ATPase.}},
    DOI = {{10.1038/nature09309}},
    ISSN = {{0028-0836}},
    EISSN = {{1476-4687}},
    ResearcherID-Numbers = {{Nissen, Poul/D-5774-2014
    Morth, Jens Preben/G-4450-2013
    }},
    ORCID-Numbers = {{Morth, Jens Preben/0000-0003-4077-0192
    Khandelia, Himanshu/0000-0001-9913-6394
    Bublitz, Maike/0000-0003-3161-418X
    Mouritsen, Ole G./0000-0002-4258-8960
    Nissen, Poul/0000-0003-0948-6628}},
    Unique-ID = {{ISI:000281461200043}},
    }
  • [DOI] H. Khandelia, M. O. Jensen, and O. G. Mouritsen, “To Gate or Not To Gate: Using Molecular Dynamics Simulations To Morph Gated Plant Aquaporins into Constitutively Open Conformations,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. {113}, iss. {15}, p. {5239-5244}, {2009}.
    [Bibtex]
    @article{ ISI:000265030500036,
    Author = {Khandelia, Himanshu and Jensen, Morten O. and Mouritsen, Ole G.},
    Title = {{To Gate or Not To Gate: Using Molecular Dynamics Simulations To Morph
    Gated Plant Aquaporins into Constitutively Open Conformations}},
    Journal = {{JOURNAL OF PHYSICAL CHEMISTRY B}},
    Year = {{2009}},
    Volume = {{113}},
    Number = {{15}},
    Pages = {{5239-5244}},
    Month = {{APR 16}},
    Abstract = {{The spinach plant aquaporin SoPIP2;1 is a gated water channel, which
    switches between open and closed states depending oil the conformation
    of a 20-residue cytoplasmic loop, the D-loop. Using fully atomistic
    molecular dynamics simulations, we have investigated the possibility of
    driving the conformational equilibrium of the protein toward a
    constitutively open state. We introduce two separate Mutations in the
    D-loop, while being in the closed conformation. We show that the single
    channel permeability of both mutants is comparable to that of the open
    conformation. This Article provides new molecular insight into the
    gating mechanism of SoPIP2;1. It is proposed that residues Arg190,
    Asp191, and Ser36 might play important roles in the gating of the
    protein.}},
    DOI = {{10.1021/jp809152c}},
    ISSN = {{1520-6106}},
    ORCID-Numbers = {{Mouritsen, Ole G./0000-0002-4258-8960
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000265030500036}},
    }
  • [DOI] H. Khandelia and O. G. Mouritsen, “Lipid Gymnastics: Evidence of Complete Acyl Chain Reversal in Oxidized Phospholipids from Molecular Simulations,” BIOPHYSICAL JOURNAL, vol. {96}, iss. {7}, p. {2734-2743}, {2009}.
    [Bibtex]
    @article{ ISI:000266376900018,
    Author = {Khandelia, Himanshu and Mouritsen, Ole G.},
    Title = {{Lipid Gymnastics: Evidence of Complete Acyl Chain Reversal in Oxidized
    Phospholipids from Molecular Simulations}},
    Journal = {{BIOPHYSICAL JOURNAL}},
    Year = {{2009}},
    Volume = {{96}},
    Number = {{7}},
    Pages = {{2734-2743}},
    Month = {{APR 8}},
    Abstract = {{In oxidative environments, biomembranes contain oxidized lipids with
    short, polar acyl chains. Two stable lipid oxidation products are
    PoxnoPC and PazePC. PoxnoPC has a carbonyl group, and PazePC has an
    anionic carboxyl group pendant at the end of the short, oxidized acyl
    chain. We have used MD simulations to explore the possibility of
    complete chain reversal in OXPLs in POPC-OXPL mixtures. The polar AZ
    chain of PazePC undergoes chain reversal without compromising the lipid
    bilayer integrity at concentrations up to 25\% OXPL, and the carboxyl
    group points into the aqueous phase. Counterintuitively, the
    perturbation of overall membrane structural and dynamic properties is
    stronger for PoxnoPC than for PazePC. This is because of the overall
    condensing and ordering effect of sodium ions bound strongly to the
    lipids in the PazePC simulations. The reorientation of AZ chain is
    similar for two different lipid force fields. This work provides the
    first molecular evidence of the ``extended lipid conformation{''} in
    phospholipid membranes. The chain reversal of PazePC lipids decorates
    the membrane interface with reactive, negatively charged functional
    groups. Such chain reversal is likely to exert a profound influence on
    the structure and dynamics of biological membranes, and on
    membrane-associated biological processes.}},
    DOI = {{10.1016/j.bpj.2009.01.007}},
    ISSN = {{0006-3495}},
    EISSN = {{1542-0086}},
    ORCID-Numbers = {{Mouritsen, Ole G./0000-0002-4258-8960
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000266376900018}},
    }
  • [DOI] A. Sayyed-Ahmad, H. Khandelia, and Y. N. Kaznessis, “Relative free energy of binding between antimicrobial peptides and SDS or DPC micelles,” MOLECULAR SIMULATION, vol. {35}, iss. {10-11}, p. {986-997}, {2009}.
    [Bibtex]
    @article{ ISI:000269789900022,
    Author = {Sayyed-Ahmad, Abdallah and Khandelia, Himanshu and Kaznessis, Yiannis N.},
    Title = {{Relative free energy of binding between antimicrobial peptides and SDS
    or DPC micelles}},
    Journal = {{MOLECULAR SIMULATION}},
    Year = {{2009}},
    Volume = {{35}},
    Number = {{10-11}},
    Pages = {{986-997}},
    Note = {{Annual Meeting of the American-Institute-of-Chemical-Engineers,
    Philadelphia, PA, NOV, 2008}},
    Organization = {{AICHE}},
    Abstract = {{We present relative binding free energy calculations for six
    antimicrobial peptide-micelle systems, three peptides interacting with
    two types of micelles. The peptides are the scorpion derived
    antimicrobial peptide (AMP), IsCT and two of its analogues. The micelles
    are dodecylphosphatidylcholine (DPC) and sodium dodecylsulphate (SDS)
    micelles. The interfacial electrostatic properties of DPC and SDS
    micelles are assumed to be similar to those of zwitterionic mammalian
    and anionic bacterial membrane interfaces, respectively. We test the
    hypothesis that the binding strength between peptides and the anionic
    micelle SDS can provide information on peptide antimicrobial activity,
    since it is widely accepted that AMPs function by binding to and
    disrupting the predominantly anionic lipid bilayer of the bacterial
    cytoplasmic membrane. We also test the hypothesis that the binding
    strength between peptides and the zwitterionic micelle DPC can provide
    information on peptide haemolytic activities, since it is accepted that
    they also bind to and disrupt the zwitterionic membrane of mammalian
    cells. Equilibrium structures of the peptides, micelles and
    peptide-micelle complexes are obtained from more than 300 ns of
    molecular dynamics simulations. A thermodynamic cycle is introduced to
    compute the binding free energy from electrostatic, non-electrostatic
    and entropic contributions. We find relative binding free energy
    strengths between peptides and SDS to correlate with the experimentally
    measured rankings for peptide antimicrobial activities, and relative
    free energy binding strengths between peptides and DPC to correlate with
    the observed rankings for peptide haemolytic toxicities. These findings
    point to the importance of peptide-membrane binding strength for
    antimicrobial activity and haemolytic activity.}},
    DOI = {{10.1080/08927020902902742}},
    ISSN = {{0892-7022}},
    EISSN = {{1029-0435}},
    ResearcherID-Numbers = {{, Asa/W-3080-2019
    Kaznessis, Yiannis N/H-1795-2015
    }},
    ORCID-Numbers = {{, Asa/0000-0003-2415-8403
    Kaznessis, Yiannis/0000-0002-5088-1104
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000269789900022}},
    }
  • [DOI] M. J. Parry, J. I. Alakoskela, H. Khandelia, S. A. Kumar, M. Jaattela, A. K. Mahalka, and P. K. J. Kinnunen, “High-affinity small molecule-phospholipid complex formation: Binding of siramesine to phosphatidic acid,” JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. {130}, iss. {39}, p. {12953-12960}, {2008}.
    [Bibtex]
    @article{ ISI:000259553700039,
    Author = {Parry, Mikko J. and Alakoskela, Juha-Matti I. and Khandelia, Himanshu
    and Kumar, Subramanian Arun and Jaattela, Marja and Mahalka, Ajay K. and
    Kinnunen, Paavo K. J.},
    Title = {{High-affinity small molecule-phospholipid complex formation: Binding of
    siramesine to phosphatidic acid}},
    Journal = {{JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}},
    Year = {{2008}},
    Volume = {{130}},
    Number = {{39}},
    Pages = {{12953-12960}},
    Month = {{OCT 1}},
    Abstract = {{Siramesine (SRM) is a sigma-2 receptor agonist which has been recently
    shown to inhibit growth of cancer cells. Fluorescence spectroscopy
    experiments revealed two distinct binding sites for this drug in
    phospholipid membranes. More specifically, acidic phospholipids retain
    siramesine on the bilayer surface due to a high-affinity interaction,
    reaching saturation at an apparent 1:1 drug-acidic phospholipid
    stoichiometry, where after the drug penetrates into the hydrocarbon core
    of the membrane. This behavior was confirmed using Langmuir films. Of
    the anionic phospholipids, the highest affinity, comparable to the
    affinities for the binding of small molecule ligands to proteins, was
    measured for phosphatidic acid (PA, mole fraction Of X-PA = 0.2 in
    phosphatidylcholine vesicles), yielding a molecular partition
    coefficient of 240 +/- 80 x 10(6). An MD simulation on the siramesine:PA
    interaction was in agreement with the above data. Taking into account
    the key role of PA as a signaling molecule promoting cell growth our
    results suggest a new paradigm for the development of anticancer drugs,
    viz. design of small molecules specifically scavenging phospholipids
    involved in the signaling cascades controlling cell behavior.}},
    DOI = {{10.1021/ja800516w}},
    ISSN = {{0002-7863}},
    ResearcherID-Numbers = {{Mahalka, Ajay Kumar/G-6875-2012
    Mahalka, Ajay/K-3993-2015
    }},
    ORCID-Numbers = {{Mahalka, Ajay Kumar/0000-0002-0716-9947
    Jaattela, Marja/0000-0001-5950-7111
    Khandelia, Himanshu/0000-0001-9913-6394
    Subramanian, Arun Kumar/0000-0003-4540-1265
    Alakoskela, Juha-Matti/0000-0002-7358-038X}},
    Unique-ID = {{ISI:000259553700039}},
    }
  • [DOI] H. Khandelia, J. H. Ipsen, and O. G. Mouritsen, “The impact of peptides on lipid membranes,” BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, vol. {1778}, iss. {7-8}, p. {1528-1536}, {2008}.
    [Bibtex]
    @article{ ISI:000257606900002,
    Author = {Khandelia, Himanshu and Ipsen, John H. and Mouritsen, Ole G.},
    Title = {{The impact of peptides on lipid membranes}},
    Journal = {{BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES}},
    Year = {{2008}},
    Volume = {{1778}},
    Number = {{7-8}},
    Pages = {{1528-1536}},
    Month = {{JUL-AUG}},
    Abstract = {{We review the fundamental strategies used by small peptides to associate
    with lipid membranes and how the different strategies impact on the
    structure and dynamics of the lipids. In particular we focus on the
    binding of amphiphilic peptides by electrostatic and hydrophobic forces,
    on the anchoring of peptides to the bilayer by acylation and
    prenylation, and on the incorporation of small peptides that form
    well-defined channels. The effect of lipid-peptide interactions on the
    lipids is characterized in terms of lipid acyl-chain order, membrane
    thickness, membrane elasticity, permeability, lipid-domain and annulus
    formation, as well as acyl-chain dynamics. The different situations are
    illustrated by specific cases for which experimental observations can be
    interpreted and supplemented by theoretical modeling and simulations. A
    comparison is made with the effect on lipids of trans-membrane proteins.
    The various cases are discussed in the context of the possible roles
    played by lipid-peptide interactions for the biological, physiological,
    and pharmacological function of peptides. (c) 2008 Elsevier B.V. All
    rights reserved.}},
    DOI = {{10.1016/j.bbamem.2008.02.009}},
    ISSN = {{0005-2736}},
    EISSN = {{1879-2642}},
    ResearcherID-Numbers = {{Ipsen, John/X-3216-2019
    }},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Ipsen, John/0000-0002-1268-6180
    Mouritsen, Ole G./0000-0002-4258-8960}},
    Unique-ID = {{ISI:000257606900002}},
    }
  • [DOI] A. A. Langham, H. Khandelia, B. Schuster, A. J. Waring, R. I. Lehrer, and Y. N. Kaznessis, “Correlation between simulated physicochemical properties and hemolycity of protegrin-like antimicrobial peptides: Predicting experimental toxicity,” PEPTIDES, vol. {29}, iss. {7}, p. {1085-1093}, {2008}.
    [Bibtex]
    @article{ ISI:000257489100002,
    Author = {Langham, Allison A. and Khandelia, Himanshu and Schuster, Benjamin and
    Waring, Alan J. and Lehrer, Robert I. and Kaznessis, Yiannis N.},
    Title = {{Correlation between simulated physicochemical properties and hemolycity
    of protegrin-like antimicrobial peptides: Predicting experimental
    toxicity}},
    Journal = {{PEPTIDES}},
    Year = {{2008}},
    Volume = {{29}},
    Number = {{7}},
    Pages = {{1085-1093}},
    Month = {{JUL}},
    Abstract = {{The therapeutic, antibiotic potential of antimicrobial peptides can be
    prohibitively diminished because of the cytotoxicity and hemolytic
    profiles they exhibit. Quantifying and predicting antimicrobial peptide
    toxicity against host cells is thus an important goal of AMP related
    research. In this work, we present quantitative structure activity
    relationships for toxicity of protegrin-like antimicrobial peptides
    against human cells (epithelial and red blood cells) based on
    physicochemical properties, such as interaction energies and radius of
    gyration, calculated from molecular dynamics simulations of the peptides
    in aqueous solvent. The hypothesis is that physicochemical properties of
    peptides, as manifest by their structure and interactions in a solvent
    and as captured by atomistic simulations, are responsible for their
    toxicity against human cells. Protegrins are beta-hairpin peptides with
    high activity against a wide variety of microbial species, but in their
    native state are toxic to human cells. Sixty peptides with
    experimentally determined toxicities were used to develop the models. We
    test the resulting relationships to determine their ability to predict
    the toxicity of several protegrin-like peptides. The developed QSARs
    provide insight into the mechanism of cytotoxic action of antimicrobial
    peptides. In a subsequent blind test, the QSAR correctly ranked four of
    five protegrin analogues newly synthesized and tested for toxicity. (C)
    2008 Elsevier Inc. All rights reserved.}},
    DOI = {{10.1016/j.peptides.2008.03.018}},
    ISSN = {{0196-9781}},
    EISSN = {{1873-5169}},
    ResearcherID-Numbers = {{Kaznessis, Yiannis N/H-1795-2015
    }},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Langham-Putrow, Allison/0000-0003-0196-7224
    Kaznessis, Yiannis/0000-0002-5088-1104}},
    Unique-ID = {{ISI:000257489100002}},
    }
  • [DOI] H. Khandelia and Y. N. Kaznessis, “Structure of the antimicrobial beta-hairpin peptide protegrin-1 in a DLPC lipid bilayer investigated by molecular dynamics simulation,” BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, vol. {1768}, iss. {3}, p. {509-520}, {2007}.
    [Bibtex]
    @article{ ISI:000245060200015,
    Author = {Khandelia, Himanshu and Kaznessis, Yiannis N.},
    Title = {{Structure of the antimicrobial beta-hairpin peptide protegrin-1 in a
    DLPC lipid bilayer investigated by molecular dynamics simulation}},
    Journal = {{BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES}},
    Year = {{2007}},
    Volume = {{1768}},
    Number = {{3}},
    Pages = {{509-520}},
    Month = {{MAR}},
    Abstract = {{All atom molecular dynamics simulations of the 18-residue beta-hairpin
    antimicrobial peptide protegrin-1 (PG-1, RGGRLCYCRRRFCVCVGR-NH2) in a
    fully hydrated dilauroylphosphatidylcholine (DLPC) lipid bilayer have
    been implemented. The goal of the reported work is to investigate the
    structure of the peptide in a membrane environment (previously solved
    only in solution {[}R.L. Fahrner, T. Dieckmann, S.S.L. Harwig, R.I.
    Lehrer, D. Eisenberg, J. Feigon, Solution structure of protegrin-1, a
    broad-spectrum antimicrobial peptide from porcine leukocytes. Chemistry
    and Biology, 3 (1996) 543-550]), and to delineate specific
    peptide-membrane interactions which are responsible for the peptide's
    membrane binding properties. A novel, previously unknown, ``kick{''}
    shaped conformation of the peptide was detected, where a bend at the
    C-terminal beta-strand of the peptide caused the peptide backbone at
    residues 16-18 to extend perpendicular to the beta-hairpin plane. This
    bend was driven by a highly persistent hydrogen-bond between the polar
    peptide side-chain of TYR7 and the unshielded backbone carbonyl oxygen
    atom of GLY17. The H-bond formation relieves the unfavorable free energy
    of insertion of polar groups into the hydrophobic membrane core. PG-1
    was anchored to the membrane by strong electrostatic binding of the
    protonated N-terminus of the peptide to the lipid head group phosphate
    anions. The orientation of the peptide in the membrane, and its
    influence on bilayer structural and dynamic properties are in excellent
    agreement with solid state NMR measurements {[}S. Yamaguchi, T. Hong, A.
    Waring, R.I. Lehrer, M. Hong, Solid-State NMR Investigations of
    Peptide-Lipid interaction and Orientation of a b-Sheet Antimicrobial
    Peptide, Protegrin, Biochemistry, 41 (2002) 9852-9862]. Importantly, two
    simulations which started from different initial orientations of the
    peptide converged to the same final equilibrium orientation of the
    peptide relative to the bilayer. The kick-shaped conformation was
    observed only in one of the two simulations. (c) 2006 Elsevier B.V. All
    rights reserved.}},
    DOI = {{10.1016/j.bbamem.2006.11.015}},
    ISSN = {{0005-2736}},
    EISSN = {{1879-2642}},
    ResearcherID-Numbers = {{Kaznessis, Yiannis N/H-1795-2015
    }},
    ORCID-Numbers = {{Kaznessis, Yiannis/0000-0002-5088-1104
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000245060200015}},
    }
  • [DOI] H. Khandelia and Y. N. Kaznessis, “Cation-pi interactions stabilize the structure of the antimicrobial peptide indolicidin near membranes: Molecular dynamics simulations,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. {111}, iss. {1}, p. {242-250}, {2007}.
    [Bibtex]
    @article{ ISI:000243229400028,
    Author = {Khandelia, Himanshu and Kaznessis, Yiannis N.},
    Title = {{Cation-pi interactions stabilize the structure of the antimicrobial
    peptide indolicidin near membranes: Molecular dynamics simulations}},
    Journal = {{JOURNAL OF PHYSICAL CHEMISTRY B}},
    Year = {{2007}},
    Volume = {{111}},
    Number = {{1}},
    Pages = {{242-250}},
    Month = {{JAN 11}},
    Abstract = {{We implemented molecular dynamics simulations of the 13-residue
    antimicrobial peptide indolicidin (ILPWKWPWWPWRR-NH2) in
    dodecylphosphocholine (DPC) and sodium dodecyl sulfate (SDS) micelles.
    In DPC, a persistent cation-pi interaction between TRP11 and ARG13
    defined the structure of the peptide near the interface. A transient
    cation-pi interaction was also observed between TRP4 and the choline
    group on DPC lipids. We also implemented simulation of a mutant of
    indolicidin in the DPC micelle where TRP11 was replaced by ALA11. As a
    result of the mutation, the boat-shaped conformation is lost and the
    structure becomes significantly less defined. On the basis of this
    evidence, we argue that cation-pi interactions determine the
    experimentally measured, well-defined boat-shaped structure of
    indolicidin. In SDS, the lack of such interactions and the electrostatic
    binding of the terminal arginine residues to the sulfate groups leads to
    an extended peptide structure. To the best of our knowledge, this is the
    first time that a cation-pi interaction between peptide side chains has
    been shown to stabilize the structure of a small antimicrobial peptide.
    The simulations are in excellent agreement with available experimental
    measurements: the backbone of the peptide is more ordered in DPC than in
    SDS; the tryptophan side chains pack against the backbone in DPC and
    point away from the backbone in SDS; the rms fluctuation of the peptide
    backbone and peptide side chains is greater in SDS than in DPC; and the
    peptide backbone order parameters are higher in DPC than in SDS.}},
    DOI = {{10.1021/jp064776j}},
    ISSN = {{1520-6106}},
    EISSN = {{1520-5207}},
    ResearcherID-Numbers = {{Kaznessis, Yiannis N/H-1795-2015
    }},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Kaznessis, Yiannis/0000-0002-5088-1104}},
    Unique-ID = {{ISI:000243229400028}},
    }
  • [DOI] H. Khandelia, A. A. Langham, and Y. N. Kaznessis, “Driving engineering of novel antimicrobial peptides from simulations of peptide-micelle interactions,” BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, vol. {1758}, iss. {9}, p. {1224-1234}, {2006}.
    [Bibtex]
    @article{ ISI:000241523100006,
    Author = {Khandelia, Himanshu and Langham, Allison A. and Kaznessis, Yiannis N.},
    Title = {{Driving engineering of novel antimicrobial peptides from simulations of
    peptide-micelle interactions}},
    Journal = {{BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES}},
    Year = {{2006}},
    Volume = {{1758}},
    Number = {{9}},
    Pages = {{1224-1234}},
    Month = {{SEP}},
    Abstract = {{Simulations of antimicrobial peptides in membrane mimics can provide the
    high resolution, atomistic picture that is necessary to decipher which
    sequence and structure components are responsible for activity and
    toxicity. With such detailed insight, engineering new sequences that are
    active but non-toxic can, in principle, be rationalized. Armed with
    supercomputers and accurate force fields for biomolecular interactions,
    we can now investigate phenomena that span hundreds of nanoseconds.
    Although the phenomena involved in antimicrobial activity, (i.e.,
    diffusion of peptides, interaction with lipid layers, secondary
    structure attainment, possible surface aggregation, possible formation
    of pores, and destruction of the lipid layer integrity) collectively
    span time scales still prohibitively long for classical mechanics
    simulations, it is now feasible to investigate the initial approach of
    single peptides and their interaction with membrane mimics. In this
    article, we discuss the promise and the challenges of widely used models
    and detail our recent work on peptide-micelle simulations as an
    attractive alternative to peptide-bilayer simulations. We detail our
    results with two large structural classes of peptides, helical and
    beta-sheet and demonstrate how simulations can assist in engineering of
    novel antimicrobials with therapeutic potential. (c) 2006 Elsevier B.V.
    All rights reserved.}},
    DOI = {{10.1016/j.bbamem.2006.03.010}},
    ISSN = {{0005-2736}},
    EISSN = {{0006-3002}},
    ResearcherID-Numbers = {{Kaznessis, Yiannis N/H-1795-2015
    }},
    ORCID-Numbers = {{Langham-Putrow, Allison/0000-0003-0196-7224
    Kaznessis, Yiannis/0000-0002-5088-1104
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000241523100006}},
    }
  • [DOI] H. Khandelia and Y. N. Kaznessis, “Molecular dynamics investigation of the influence of anionic and zwitterionic interfaces on antimicrobial peptides’ structure: Implications for peptide toxicity and activity,” PEPTIDES, vol. {27}, iss. {6}, p. {1192-1200}, {2006}.
    [Bibtex]
    @article{ ISI:000238455600005,
    Author = {Khandelia, Himanshu and Kaznessis, Yiannis N.},
    Title = {{Molecular dynamics investigation of the influence of anionic and
    zwitterionic interfaces on antimicrobial peptides' structure:
    Implications for peptide toxicity and activity}},
    Journal = {{PEPTIDES}},
    Year = {{2006}},
    Volume = {{27}},
    Number = {{6}},
    Pages = {{1192-1200}},
    Month = {{JUN}},
    Abstract = {{Molecular dynamics simulations of three related helical antimicrobial
    peptides have been carried out in zwitterionic diphosphocholine (DPC)
    micelles and anionic sodiumdodecylsulfate (SDS) micelles. These systems
    can be considered as model mammalian and bacterial membrane interfaces,
    respectively. The goal of this study is to dissect the differences in
    peptide composition which make the mutant peptides (novispirin-G10 and
    novispirin-T7) less toxic than the parent peptide ovispirin (OVIS),
    although all three peptides have highly antibacterial properties.
    Compared to G10 and T7, OVIS inserts deepest into the DPC micelle. This
    correlates well with the lesser toxicity of G10 and T7. There is strong
    evidence which suggests that synergistic binding of hydrophobic residues
    drives binding of OVIS to the micelle. The helical content of G10 and T7
    is reduced in the presence of DPC, and this leads to less amphipathic
    peptide structures, which bind weakly to the micelle. Simulations in SDS
    were carried out to compare the influence of membrane electrostatics on
    peptide structure. All three peptides bound strongly to SDS, and
    retained helical form. This corresponds well with their equally potent
    antibacterial properties. Based on the simulations, we argue that
    secondary structure stability often leads to toxic properties. We also
    propose that G10 and T7 operate by the carpet mechanism of cell lysis.
    Toxicity of peptides operating by the carpet mechanism can be attenuated
    by reducing the peptide helical content. The simulations successfully
    capture experimental binding states, and the different depths of binding
    of the three peptides to the two micelles correlate with their
    antibacterial and toxic properties. (c) 2005 Elsevier Inc. All rights
    reserved.}},
    DOI = {{10.1016/j.peptides.2005.10.022}},
    ISSN = {{0196-9781}},
    EISSN = {{1873-5169}},
    ResearcherID-Numbers = {{Kaznessis, Yiannis N/H-1795-2015
    }},
    ORCID-Numbers = {{Kaznessis, Yiannis/0000-0002-5088-1104
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000238455600005}},
    }
  • [DOI] A. Langham, H. Khandelia, and Y. Kaznessis, “How can a beta-sheet peptide be both a potent antimicrobial and harmfully toxic? Molecular dynamics simulations of protegrin-1 in micelles,” BIOPOLYMERS, vol. {84}, iss. {2}, p. {219-231}, {2006}.
    [Bibtex]
    @article{ ISI:000236389000008,
    Author = {Langham, AA and Khandelia, H and Kaznessis, YN},
    Title = {{How can a beta-sheet peptide be both a potent antimicrobial and
    harmfully toxic? Molecular dynamics simulations of protegrin-1 in
    micelles}},
    Journal = {{BIOPOLYMERS}},
    Year = {{2006}},
    Volume = {{84}},
    Number = {{2}},
    Pages = {{219-231}},
    Abstract = {{In this work, the naturally occurring beta-hairpin antimicrobial peptide
    protegrin-1 (PG-1) is studied by molecular dynamics simulation ill
    all-atom sodium dodecylsulfate and dodecylphosphocholine micelles. These
    simulations provide a high-resolution picture of the interactions
    between the peptide and simple models of bacterial and mammalian
    membranes. Both micelles show significant disruption, as is expected for
    a peptide that is both active against bacteria and toxic to host cells.
    There is, however, clear differentiation between the behavior ill SDS
    versus DPC, which suggests difftent mechanisms of interaction for PG-I
    with mammalian and bacterial membranes. Specifically, the equilibrium
    orientation of the peptide relative to SDS is a mirror image of its
    position relative to DPC. In both systems, the arginine residues of PG-I
    strongly interact with the head groups of the micelles. In DPC, the
    peptide prefers a location closer to the core of the micelle with
    Phe(12) Val(14) and Val(16) imbedded ill the core and the other side of
    the hairpin, which includes Leu(5) and Tyr(7), located closer to the
    surface of the micelle. In SDS, the peptide prefers a location at the
    micelle-water interface. The peptide position is reversed, with Leu(5)
    and Cys(6) imbedded furthest in the micelle core and Phe (12), Val(14),
    and Val(16) on the surface of the micelle. We discuss the implications
    of these results with respect to activity and toxicity. (c) 2005 Wiley
    Periodicals, Inc.}},
    DOI = {{10.1002/bip.20397}},
    ISSN = {{0006-3525}},
    EISSN = {{1097-0282}},
    ResearcherID-Numbers = {{Kaznessis, Yiannis N/H-1795-2015
    }},
    ORCID-Numbers = {{Kaznessis, Yiannis/0000-0002-5088-1104
    Khandelia, Himanshu/0000-0001-9913-6394
    Langham-Putrow, Allison/0000-0003-0196-7224}},
    Unique-ID = {{ISI:000236389000008}},
    }
  • [DOI] H. Khandelia and Y. Kaznessis, “Molecular dynamics simulations of helical antimicrobial peptides in SDS micelles: What do point mutations achieve?,” PEPTIDES, vol. {26}, iss. {11}, p. {2037-2049}, {2005}.
    [Bibtex]
    @article{ ISI:000233373100001,
    Author = {Khandelia, H and Kaznessis, YN},
    Title = {{Molecular dynamics simulations of helical antimicrobial peptides in SDS
    micelles: What do point mutations achieve?}},
    Journal = {{PEPTIDES}},
    Year = {{2005}},
    Volume = {{26}},
    Number = {{11}},
    Pages = {{2037-2049}},
    Month = {{NOV}},
    Abstract = {{We report long time scale simulations of the 18-residue helical
    antimicrobial peptide ovispirin-1 and its analogs novispirin-G10 and
    novispirin-T7 in SDS micelles. The SDS micelle serves as an economical
    and effective model for a cellular membrane. Ovispirin, which is
    initially placed along a micelle diameter, diffuses out to the water-SDS
    interface and stabilizes to an interface-bound steady state in 16:35 ns
    of simulation. The final conformation, orientation, and the structure of
    ovispirin are in good agreement with the experimentally observed
    properties of the peptide in presence of lipid bilayers. The simulation
    succeeds in capturing subtle differences of the membrane-bound peptide
    structure as predicted by solid state NMR. The novispirins also undergo
    identical diffusion patterns and similar final conformations. Although
    the final interface-bound states are similar, the simulations illuminate
    the structural and binding properties of the mutant peptides which make
    them less toxic compared to ovispirin. Based on previous data and the
    current simulations, we propose that introduction of a bend/hinge at the
    center of helical antimicrobial peptides (containing a specific
    C-terminal motif), without disrupting the helicity of the peptides might
    attenuate host-cell toxicity as well as improve membrane binding
    properties to bacterial cellular envelopes. (c) 2005 Elsevier Inc. All
    rights reserved.}},
    DOI = {{10.1016/j.peptides.2005.03.058}},
    ISSN = {{0196-9781}},
    EISSN = {{1873-5169}},
    ResearcherID-Numbers = {{Kaznessis, Yiannis N/H-1795-2015
    }},
    ORCID-Numbers = {{Kaznessis, Yiannis/0000-0002-5088-1104
    Khandelia, Himanshu/0000-0001-9913-6394}},
    Unique-ID = {{ISI:000233373100001}},
    }
  • [DOI] H. Khandelia and Y. Kaznessis, “Molecular dynamics simulations of the helical antimicrobial peptide ovispirin-1 in a zwitterionic dodecylphosphocholine micelle: Insights into host-cell toxicity,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. {109}, iss. {26}, p. {12990-12996}, {2005}.
    [Bibtex]
    @article{ ISI:000230224700048,
    Author = {Khandelia, H and Kaznessis, YN},
    Title = {{Molecular dynamics simulations of the helical antimicrobial peptide
    ovispirin-1 in a zwitterionic dodecylphosphocholine micelle: Insights
    into host-cell toxicity}},
    Journal = {{JOURNAL OF PHYSICAL CHEMISTRY B}},
    Year = {{2005}},
    Volume = {{109}},
    Number = {{26}},
    Pages = {{12990-12996}},
    Month = {{JUL 7}},
    Abstract = {{We have carried out a 40-ns all-atom molecular dynamics simulation of
    the helical antimicrobial peptide ovispirin-1 (OVIS) in a zwittcrionic
    diphosphocholine (DPC) micelle. The DPC micelle serves as an economical
    and effective model for a cellular membrane owing to the presence of a
    choline headgroup, which resembles those of membrane phospholipids.
    OVIS, which was initially placed along a micelle diameter, diffuses out
    to the water-DPC interface, and the simulation stabilizes to an
    interface-bound steady state in 40 ns. The helical content of the
    peptide marginally increases in the process. The final conformation,
    orientation, and the structure of OVIS are in excellent agreement with
    the experimentally observed properties of the peptide in the presence of
    lipid bilayers composed of 75\% zwitterionic lipids. The amphipathic
    peptide binds to the micelle with its hydrophobic face buried in the
    micellar core and the polar side chains protruding into the aqueous
    phase. There is overwhelming evidence that points to the significant and
    indispensable participation of hydrophobic residues in binding to the
    zwitterionic interface. The simulation starts with a conformation that
    is unbiased toward the final experimentally known binding state of the
    peptide. The ability of the model to reproduce experimental binding
    states despite this starting conformation is encouraging.}},
    DOI = {{10.1021/jp050162n}},
    ISSN = {{1520-6106}},
    EISSN = {{1520-5207}},
    ResearcherID-Numbers = {{Kaznessis, Yiannis N/H-1795-2015
    }},
    ORCID-Numbers = {{Khandelia, Himanshu/0000-0001-9913-6394
    Kaznessis, Yiannis/0000-0002-5088-1104}},
    Unique-ID = {{ISI:000230224700048}},
    }