George Khelashvili, Ph.D.

Assistant Professor of Research in Physiology and Biophysics

  • Assistant Professor of Research in Computational Biophysics in the Institute for Computational Biomedicine

212-746-6348

1300 York Avenue, Room LC-501A
New York, NY 10065


Techniques

Research Areas


Research Summary:

The overall goal of the research projects in the lab is to uncover dynamic mechanisms in fundamental biological processes of signal transduction by cell surface proteins in the categories of receptors (such as G protein-coupled receptors, GPCRs), transporters in the family of Neurotransmitter:Sodium-Symporters (NSS), and lipid scramblases. Special emphasis is on understanding how the spatial organization and function of these molecular machines are regulated by the cell membrane, its components (i.e. cholesterol, various lipids), and interactions with the rich environment of the cell’s proteins. We approach these research topics with advanced quantitative methods of theoretical and computational biophysics, developed and utilized at the highest level of each specialty. We pursue interdisciplinary and multi-scale strategies that integrate biophysical theory and computation with biophysical measurements and molecular cell biology experimentation. Our approach takes advantage of an abundance of molecular level insights from experimental explorations of the function and interactions of membrane-associated signaling proteins, and interprets them in a novel quantitative multi-scale framework to yield insights based on energetics, and experimentally testable hypotheses we validate with respect to mechanisms by which membrane properties and remodeling (e.g. curvature, lipid segregation) affect protein function, organization and signaling-associated interactions that are of major importance to cell physiology.

Recent Publications:

  1. Plante, A, Shore, DM, Morra, G, Khelashvili, G, Weinstein, H. A Machine Learning Approach for the Discovery of Ligand-Specific Functional Mechanisms of GPCRs. Molecules. 2019;24 (11):. doi: 10.3390/molecules24112097. PubMed PMID:31159491 .
  2. Doktorova, M, LeVine, MV, Khelashvili, G, Weinstein, H. A New Computational Method for Membrane Compressibility: Bilayer Mechanical Thickness Revisited. Biophys. J. 2019;116 (3):487-502. doi: 10.1016/j.bpj.2018.12.016. PubMed PMID:30665693 PubMed Central PMC6369663.
  3. Khelashvili, G. Mesoscale Computational Modeling of Protein-Membrane Interactions Based on Continuum Mean-Field Theory. Methods Mol. Biol. 2019;1860 :15-31. doi: 10.1007/978-1-4939-8760-3_2. PubMed PMID:30317496 .
  4. Lee, BC, Khelashvili, G, Falzone, M, Menon, AK, Weinstein, H, Accardi, A et al.. Gating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase. Nat Commun. 2018;9 (1):3251. doi: 10.1038/s41467-018-05724-1. PubMed PMID:30108217 PubMed Central PMC6092359.
  5. Herlo, R, Lund, VK, Lycas, MD, Jansen, AM, Khelashvili, G, Andersen, RC et al.. An Amphipathic Helix Directs Cellular Membrane Curvature Sensing and Function of the BAR Domain Protein PICK1. Cell Rep. 2018;23 (7):2056-2069. doi: 10.1016/j.celrep.2018.04.074. PubMed PMID:29768204 .
  6. Razavi, AM, Khelashvili, G, Weinstein, H. How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties. BMC Biol. 2018;16 (1):31. doi: 10.1186/s12915-018-0495-6. PubMed PMID:29540172 PubMed Central PMC5852957.
  7. Terry, DS, Kolster, RA, Quick, M, LeVine, MV, Khelashvili, G, Zhou, Z et al.. A partially-open inward-facing intermediate conformation of LeuT is associated with Na+ release and substrate transport. Nat Commun. 2018;9 (1):230. doi: 10.1038/s41467-017-02202-y. PubMed PMID:29335402 PubMed Central PMC5768729.
  8. Morra, G, Razavi, AM, Pandey, K, Weinstein, H, Menon, AK, Khelashvili, G et al.. Mechanisms of Lipid Scrambling by the G Protein-Coupled Receptor Opsin. Structure. 2018;26 (2):356-367.e3. doi: 10.1016/j.str.2017.11.020. PubMed PMID:29290486 PubMed Central PMC5803311.
  9. Pandey, K, Ploier, B, Goren, MA, Levitz, J, Khelashvili, G, Menon, AK et al.. An engineered opsin monomer scrambles phospholipids. Sci Rep. 2017;7 (1):16741. doi: 10.1038/s41598-017-16842-z. PubMed PMID:29196630 PubMed Central PMC5711885.
  10. LeVine, MV, Cuendet, MA, Razavi, AM, Khelashvili, G, Weinstein, H. Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter. Biophys. J. 2018;114 (1):10-14. doi: 10.1016/j.bpj.2017.10.030. PubMed PMID:29153319 PubMed Central PMC5773750.
  11. Doktorova, M, Heberle, FA, Kingston, RL, Khelashvili, G, Cuendet, MA, Wen, Y et al.. Cholesterol Promotes Protein Binding by Affecting Membrane Electrostatics and Solvation Properties. Biophys. J. 2017;113 (9):2004-2015. doi: 10.1016/j.bpj.2017.08.055. PubMed PMID:29117524 PubMed Central PMC5685651.
  12. Clark, LD, Dikiy, I, Chapman, K, Rödström, KE, Aramini, J, LeVine, MV et al.. Ligand modulation of sidechain dynamics in a wild-type human GPCR. Elife. 2017;6 :. doi: 10.7554/eLife.28505. PubMed PMID:28984574 PubMed Central PMC5650471.
  13. Verchère, A, Ou, WL, Ploier, B, Morizumi, T, Goren, MA, Bütikofer, P et al.. Light-independent phospholipid scramblase activity of bacteriorhodopsin from Halobacterium salinarum. Sci Rep. 2017;7 (1):9522. doi: 10.1038/s41598-017-09835-5. PubMed PMID:28842688 PubMed Central PMC5572738.
  14. Razavi, AM, Khelashvili, G, Weinstein, H. A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter. Sci Rep. 2017;7 :40076. doi: 10.1038/srep40076. PubMed PMID:28059145 PubMed Central PMC5216462.
  15. Sahai, MA, Davidson, C, Khelashvili, G, Barrese, V, Dutta, N, Weinstein, H et al.. Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2017;75 :1-9. doi: 10.1016/j.pnpbp.2016.11.004. PubMed PMID:27890676 .
  16. Khelashvili, G, Schmidt, SG, Shi, L, Javitch, JA, Gether, U, Loland, CJ et al.. Conformational Dynamics on the Extracellular Side of LeuT Controlled by Na+ and K+ Ions and the Protonation State of Glu290. J. Biol. Chem. 2016;291 (38):19786-99. doi: 10.1074/jbc.M116.731455. PubMed PMID:27474737 PubMed Central PMC5025669.
  17. Johner, N, Harries, D, Khelashvili, G. Erratum to: Implementation of a methodology for determining elastic properties of lipid assemblies from molecular dynamics simulations. BMC Bioinformatics. 2016;17 (1):236. doi: 10.1186/s12859-016-1091-9. PubMed PMID:27301431 PubMed Central PMC4908771.
  18. Johner, N, Harries, D, Khelashvili, G. Implementation of a methodology for determining elastic properties of lipid assemblies from molecular dynamics simulations. BMC Bioinformatics. 2016;17 :161. doi: 10.1186/s12859-016-1003-z. PubMed PMID:27071656 PubMed Central PMC4830014.
  19. LeVine, MV, Cuendet, MA, Khelashvili, G, Weinstein, H. Allosteric Mechanisms of Molecular Machines at the Membrane: Transport by Sodium-Coupled Symporters. Chem. Rev. 2016;116 (11):6552-87. doi: 10.1021/acs.chemrev.5b00627. PubMed PMID:26892914 .
  20. LeVine, MV, Khelashvili, G, Shi, L, Quick, M, Javitch, JA, Weinstein, H et al.. Role of Annular Lipids in the Functional Properties of Leucine Transporter LeuT Proteomicelles. Biochemistry. 2016;55 (6):850-9. doi: 10.1021/acs.biochem.5b01268. PubMed PMID:26811944 PubMed Central PMC4757857.
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