Harel Weinstein, D.Sc.

Maxwell M. Upson Professor of Physiology and Biophysics

  • Chairman of the Department of Physiology and Biophysics
  • Tri-institutional Professor (Weill Cornell Medicine, Rockefeller University, Memorial Sloan-Kettering Cancer Center)
  • Director of the Institute for Computational Biomedicine

212-746-6358
1300 York Avenue, Room E-509 F

New York, NY 10065


Techniques

Research Areas


Harel Weinstein, D.Sc. is the Maxwell Upson Professor of Physiology and Biophysics and Chairman of the Department of Physiology and Biophysics, and the Director of the Institute for Computational Biomedicine at Weill Cornell Medical College of Cornell University in New York City. As a Tri-Institutional Professor, he holds professorial appointments at Rockefeller University, Sloan-Kettering Institute and Cornell University. As the founding director of the Institute for Computational Biomedicine (ICB) he has developed it into an academic and research unit responsible for a novel approach to biomedicine that involves the mathematical, physical and computational sciences in combination with engineering and medical informatics. The ICB aims at fundamental study and practical use of the basic, quantitative understanding of physiological function and disease, in an integrative, multi-scale approach based on gene structure and defects responsible for properties and behaviors at all levels–from protein, to cell, tissue and organ. He has received numerous honors and awards, he was elected to the Executive Board of the International Society for Computational Biology in 2006, and President of the Biophysical Society in 2008. He has also served as President of the Association of Chairmen of Departments of Physiology, President of the International Society for Quantum Biology and Pharmacology, Chair of the Biophysics Section of the New York Academy of Sciences and Councilor of the Biophysical Society and of the New York Academy of Medicine. His lab is devoted to studies in molecular and computational biophysics that address complex systems in physiology, and to the development and application of bioinformatics and engineering approaches to systems biology. The Weinstein lab studies complex systems in physiology with methods of molecular and computational biophysics, bioinformatics and mathematical models. The work addresses structural and dynamic mechanisms in fundamental biological processes such as signal transduction, neuronal signaling and regulation of cell growth mechanisms, and the expression of these processes in the physiological functions of tissues and organs. Theoretical and computational methods of biophysics are combined with experimental designs to determine structural and dynamic properties at the molecular level. The processes emerging from the interaction of cellular components described at this molecular level are evaluated with computational simulations of cell function. A current theme centers on the mechanisms of molecular recognition and allostery of micromachines involved in signal transduction — specifically, how this explains macromolecular dynamics, oligomerization and encounter-complex formation in cellular signaling by G protein coupled receptors, neurotransmitter transporters and multidomain scaffolding proteins. The biomedical end points for these particular studies are neurotransmission in health and disease, drug abuse mechanisms and cancer.

Research Summary:

Molecular recognition and signal transduction

Structural, dynamic and electronic determinants of biological processes underlying physiological functions are addressed in the lab through the development and application of methods in theoretical and computational biophysics. Much of the computational and modeling efforts offer improved methods and new structural insights related to function. The approaches include theoretical determinations of molecular structure and properties, computational simulations and bioinformatics.

A particular strength of the studies is that they are carried out in collaborative arrangements with experimental explorations of cellular processes and biomolecular functions. Because the central questions emerging from research in cellular and molecular biology require functional and mechanistic interpretations at the molecular level, computational explorations complement experiments and enrich them with mechanistic insights and new testable hypotheses.

New algorithms and informatics tools have also emerged from these studies. The research is focused on the study of generalizable mechanisms such as those triggered by molecular recognition and leading to signal transduction in systems of ever increasing size and complexity.

Recent Publications:

  1. Khelashvili, G, Falzone, ME, Cheng, X, Lee, BC, Accardi, A, Weinstein, H et al.. Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca2+-bound nhTMEM16. Nat Commun. 2019;10 (1):4972. doi: 10.1038/s41467-019-12865-4. PubMed PMID:31672969 PubMed Central PMC6823365.
  2. Carrillo-Cabada, H, Benson, J, Razavi, A, Mulligan, B, Cuendet, MA, Weinstein, H et al.. A Graphic Encoding Method for Quantitative Classification of Protein Structure and Representation of Conformational Changes. IEEE/ACM Trans Comput Biol Bioinform. 2019; :. doi: 10.1109/TCBB.2019.2945291. PubMed PMID:31603792 .
  3. Doktorova, M, LeVine, MV, Khelashvili, G, Weinstein, H. A New Computational Method for Membrane Compressibility: Bilayer Mechanical Thickness Revisited. Biophys. J. 2019;117 (4):790. doi: 10.1016/j.bpj.2019.07.039. PubMed PMID:31378312 PubMed Central PMC6712547.
  4. LeVine, MV, Terry, DS, Khelashvili, G, Siegel, ZS, Quick, M, Javitch, JA et al.. The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor. Proc. Natl. Acad. Sci. U.S.A. 2019;116 (32):15947-15956. doi: 10.1073/pnas.1903020116. PubMed PMID:31324743 PubMed Central PMC6689989.
  5. 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 PubMed Central PMC6600179.
  6. Doktorova, M, Heberle, FA, Marquardt, D, Rusinova, R, Sanford, RL, Peyear, TA et al.. Gramicidin Increases Lipid Flip-Flop in Symmetric and Asymmetric Lipid Vesicles. Biophys. J. 2019;116 (5):860-873. doi: 10.1016/j.bpj.2019.01.016. PubMed PMID:30755300 PubMed Central PMC6400823.
  7. 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.
  8. Doktorova, M, Weinstein, H. Accurate In Silico Modeling of Asymmetric Bilayers Based on Biophysical Principles. Biophys. J. 2018;115 (9):1638-1643. doi: 10.1016/j.bpj.2018.09.008. PubMed PMID:30297133 PubMed Central PMC6224353.
  9. 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.
  10. Quick, M, Abramyan, AM, Wiriyasermkul, P, Weinstein, H, Shi, L, Javitch, JA et al.. The LeuT-fold neurotransmitter:sodium symporter MhsT has two substrate sites. Proc. Natl. Acad. Sci. U.S.A. 2018;115 (34):E7924-E7931. doi: 10.1073/pnas.1717444115. PubMed PMID:30082383 PubMed Central PMC6112694.
  11. 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 .
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. Gregorio, GG, Masureel, M, Hilger, D, Terry, DS, Juette, M, Zhao, H et al.. Single-molecule analysis of ligand efficacy in β2AR-G-protein activation. Nature. 2017;547 (7661):68-73. doi: 10.1038/nature22354. PubMed PMID:28607487 PubMed Central PMC5502743.
  17. Wragg, RT, Parisotto, DA, Li, Z, Terakawa, MS, Snead, D, Basu, I et al.. Evolutionary Divergence of the C-terminal Domain of Complexin Accounts for Functional Disparities between Vertebrate and Invertebrate Complexins. Front Mol Neurosci. 2017;10 :146. doi: 10.3389/fnmol.2017.00146. PubMed PMID:28603484 PubMed Central PMC5445133.
  18. Stolzenberg, S, Li, Z, Quick, M, Malinauskaite, L, Nissen, P, Weinstein, H et al.. The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state. J. Biol. Chem. 2017;292 (18):7372-7384. doi: 10.1074/jbc.M116.757153. PubMed PMID:28320858 PubMed Central PMC5418039.
  19. Li, X, Maretzky, T, Perez-Aguilar, JM, Monette, S, Weskamp, G, Le Gall, S et al.. Structural modeling defines transmembrane residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis. J. Cell. Sci. 2017;130 (5):868-878. doi: 10.1242/jcs.196436. PubMed PMID:28104813 PubMed Central PMC5358332.
  20. 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.
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