Harel Weinstein, D.Sc.
- Tri-institutional Professor (Weill Cornell Medicine, Rockefeller University, Memorial Sloan-Kettering Cancer Center)
- Director of the Institute for Computational Biomedicine
New York, NY 10065
Harel Weinstein, D.Sc. is the Maxwell Upson Professor of Physiology and Biophysics and former 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.
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.
- Xie, H, Weinstein, H. Allosterically coupled conformational dynamics in solution prepare the sterol transfer protein StarD4 to release its cargo upon interaction with target membranes. Front Mol Biosci. 2023;10 :1197154. doi: 10.3389/fmolb.2023.1197154. PubMed PMID:37275961 PubMed Central PMC10232897.
- Choi, A, Kots, ED, Singleton, DT, Weinstein, HA, Whittaker, GR. Analysis of the molecular determinants for furin cleavage of the spike protein S1/S2 site in defined strains of the prototype coronavirus murine hepatitis virus (MHV). bioRxiv. 2023; :. doi: 10.1101/2023.01.11.523687. PubMed PMID:36711446 PubMed Central PMC9882190.
- Bram, Y, Duan, X, Nilsson-Payant, BE, Chandar, V, Wu, H, Shore, D et al.. Dual-Reporter System for Real-Time Monitoring of SARS-CoV-2 Main Protease Activity in Live Cells Enables Identification of an Allosteric Inhibition Path. ACS Bio Med Chem Au. 2022;2 (6):627-641. doi: 10.1021/acsbiomedchemau.2c00034. PubMed PMID:36570071 PubMed Central PMC9603010.
- Yaron, TM, Heaton, BE, Levy, TM, Johnson, JL, Jordan, TX, Cohen, BM et al.. Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication. Sci Signal. 2022;15 (757):eabm0808. doi: 10.1126/scisignal.abm0808. PubMed PMID:36282911 PubMed Central PMC9830954.
- Khelashvili, G, Kots, E, Cheng, X, Levine, MV, Weinstein, H. The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase. Commun Biol. 2022;5 (1):990. doi: 10.1038/s42003-022-03930-8. PubMed PMID:36123525 PubMed Central PMC9484709.
- Cheng, X, Khelashvili, G, Weinstein, H. The permeation of potassium ions through the lipid scrambling path of the membrane protein nhTMEM16. Front Mol Biosci. 2022;9 :903972. doi: 10.3389/fmolb.2022.903972. PubMed PMID:35942471 PubMed Central PMC9356224.
- Osei-Owusu, J, Kots, E, Ruan, Z, Mihaljević, L, Chen, KH, Tamhaney, A et al.. Molecular determinants of pH sensing in the proton-activated chloride channel. Proc Natl Acad Sci U S A. 2022;119 (31):e2200727119. doi: 10.1073/pnas.2200727119. PubMed PMID:35878032 PubMed Central PMC9351481.
- Zhang, X, Xie, H, Iaea, D, Khelashvili, G, Weinstein, H, Maxfield, FR et al.. Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes. J Biol Chem. 2022;298 (7):102058. doi: 10.1016/j.jbc.2022.102058. PubMed PMID:35605664 PubMed Central PMC9207681.
- Kots, E, Shore, DM, Weinstein, H. Simulation of pH-Dependent Conformational Transitions in Membrane Proteins: The CLC-ec1 Cl-/H+ Antiporter. Molecules. 2021;26 (22):. doi: 10.3390/molecules26226956. PubMed PMID:34834047 PubMed Central PMC8625536.
- Heath, GR, Kots, E, Robertson, JL, Lansky, S, Khelashvili, G, Weinstein, H et al.. Localization atomic force microscopy. Nature. 2021;594 (7863):385-390. doi: 10.1038/s41586-021-03551-x. PubMed PMID:34135520 PubMed Central PMC8697813.
- Plante, A, Weinstein, H. Ligand-Dependent Conformational Transitions in Molecular Dynamics Trajectories of GPCRs Revealed by a New Machine Learning Rare Event Detection Protocol. Molecules. 2021;26 (10):. doi: 10.3390/molecules26103059. PubMed PMID:34065494 PubMed Central PMC8161244.
- Khelashvili, G, Plante, A, Doktorova, M, Weinstein, H. Ca2+-dependent mechanism of membrane insertion and destabilization by the SARS-CoV-2 fusion peptide. Biophys J. 2021;120 (6):1105-1119. doi: 10.1016/j.bpj.2021.02.023. PubMed PMID:33631204 PubMed Central PMC7899928.
- Khelashvili, G, Plante, A, Doktorova, M, Weinstein, H. Ca 2+ -dependent mechanism of membrane insertion and destabilization by the SARS-CoV-2 fusion peptide. bioRxiv. 2021; :. doi: 10.1101/2020.12.03.410472. PubMed PMID:33299996 PubMed Central PMC7724664.
- Yaron, TM, Heaton, BE, Levy, TM, Johnson, JL, Jordan, TX, Cohen, BM et al.. The FDA-approved drug Alectinib compromises SARS-CoV-2 nucleocapsid phosphorylation and inhibits viral infection in vitro. bioRxiv. 2020; :. doi: 10.1101/2020.08.14.251207. PubMed PMID:32817937 PubMed Central PMC7430567.
- Rodríguez-Espigares, I, Torrens-Fontanals, M, Tiemann, JKS, Aranda-García, D, Ramírez-Anguita, JM, Stepniewski, TM et al.. Publisher Correction: GPCRmd uncovers the dynamics of the 3D-GPCRome. Nat Methods. 2020;17 (8):861-862. doi: 10.1038/s41592-020-0928-3. PubMed PMID:32704182 .
- Rodríguez-Espigares, I, Torrens-Fontanals, M, Tiemann, JKS, Aranda-García, D, Ramírez-Anguita, JM, Stepniewski, TM et al.. GPCRmd uncovers the dynamics of the 3D-GPCRome. Nat Methods. 2020;17 (8):777-787. doi: 10.1038/s41592-020-0884-y. PubMed PMID:32661425 .
- Huang, Y, Wang, X, Lv, G, Razavi, AM, Huysmans, GHM, Weinstein, H et al.. Use of paramagnetic 19F NMR to monitor domain movement in a glutamate transporter homolog. Nat Chem Biol. 2020;16 (9):1006-1012. doi: 10.1038/s41589-020-0561-6. PubMed PMID:32514183 PubMed Central PMC7442671.
- Tang, B, Li, X, Maretzky, T, Perez-Aguilar, JM, McIlwain, D, Xie, Y et al.. Substrate-selective protein ectodomain shedding by ADAM17 and iRhom2 depends on their juxtamembrane and transmembrane domains. FASEB J. 2020;34 (4):4956-4969. doi: 10.1096/fj.201902649R. PubMed PMID:32103528 PubMed Central PMC7316530.
- Gotfryd, K, Boesen, T, Mortensen, JS, Khelashvili, G, Quick, M, Terry, DS et al.. X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release. Nat Commun. 2020;11 (1):1005. doi: 10.1038/s41467-020-14735-w. PubMed PMID:32081981 PubMed Central PMC7035281.
- Khelashvili, G, Cheng, X, Falzone, ME, Doktorova, M, Accardi, A, Weinstein, H et al.. Membrane lipids are both the substrates and a mechanistically responsive environment of TMEM16 scramblase proteins. J Comput Chem. 2020;41 (6):538-551. doi: 10.1002/jcc.26105. PubMed PMID:31750558 PubMed Central PMC7261202.