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