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Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core.
Nat Commun. 2022 02 22; 13(1):1002.NC

Abstract

The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes dissociation of the S1 domains and exposure of the fusion machinery, although the molecular details of this process have yet to be observed. We report the development of bottom-up coarse-grained (CG) models consistent with cryo-electron tomography data, and the use of CG molecular dynamics simulations to investigate viral binding and S2 core exposure. We show that spike trimers cooperatively bind to multiple ACE2 dimers at virion-cell interfaces in a manner distinct from binding between soluble proteins, which processively induces S1 dissociation. We also simulate possible variant behavior using perturbed CG models, and find that ACE2-induced S1 dissociation is primarily sensitive to conformational state populations and the extent of S1/S2 cleavage, rather than ACE2 binding affinity. These simulations reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry.

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Authors+Show Affiliations

Pak AJ
Department of Chemistry, The University of Chicago, Chicago, IL, USA. Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO, USA.
Yu A
Department of Chemistry, The University of Chicago, Chicago, IL, USA.
Ke Z
Structural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. Department of Cell and Virus Structure, Max Planck Institute of Biochemistry, Martinsried, Germany.
Briggs JAG
Structural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. Department of Cell and Virus Structure, Max Planck Institute of Biochemistry, Martinsried, Germany.
Voth GA
Department of Chemistry, The University of Chicago, Chicago, IL, USA. gavoth@uchicago.edu. Chicago Center for Theoretical Chemistry, The University of Chicago, Chicago, IL, USA. gavoth@uchicago.edu. Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA. gavoth@uchicago.edu. James Franck Institute, The University of Chicago, Chicago, IL, USA. gavoth@uchicago.edu.

MeSH

AlgorithmsAngiotensin-Converting Enzyme 2COVID-19Host-Pathogen InteractionsHumansMembrane FusionMolecular Dynamics SimulationProtein BindingProtein DomainsProtein MultimerizationReceptors, VirusSARS-CoV-2Spike Glycoprotein, CoronavirusVirus AttachmentVirus Internalization

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

35194049

Citation

Pak, Alexander J., et al. "Cooperative Multivalent Receptor Binding Promotes Exposure of the SARS-CoV-2 Fusion Machinery Core." Nature Communications, vol. 13, no. 1, 2022, p. 1002.
Pak AJ, Yu A, Ke Z, et al. Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core. Nat Commun. 2022;13(1):1002.
Pak, A. J., Yu, A., Ke, Z., Briggs, J. A. G., & Voth, G. A. (2022). Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core. Nature Communications, 13(1), 1002. https://doi.org/10.1038/s41467-022-28654-5
Pak AJ, et al. Cooperative Multivalent Receptor Binding Promotes Exposure of the SARS-CoV-2 Fusion Machinery Core. Nat Commun. 2022 02 22;13(1):1002. PubMed PMID: 35194049.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core. AU - Pak,Alexander J, AU - Yu,Alvin, AU - Ke,Zunlong, AU - Briggs,John A G, AU - Voth,Gregory A, Y1 - 2022/02/22/ PY - 2021/06/20/received PY - 2022/02/03/accepted PY - 2022/2/23/entrez PY - 2022/2/24/pubmed PY - 2022/3/8/medline SP - 1002 EP - 1002 JF - Nature communications JO - Nat Commun VL - 13 IS - 1 N2 - The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes dissociation of the S1 domains and exposure of the fusion machinery, although the molecular details of this process have yet to be observed. We report the development of bottom-up coarse-grained (CG) models consistent with cryo-electron tomography data, and the use of CG molecular dynamics simulations to investigate viral binding and S2 core exposure. We show that spike trimers cooperatively bind to multiple ACE2 dimers at virion-cell interfaces in a manner distinct from binding between soluble proteins, which processively induces S1 dissociation. We also simulate possible variant behavior using perturbed CG models, and find that ACE2-induced S1 dissociation is primarily sensitive to conformational state populations and the extent of S1/S2 cleavage, rather than ACE2 binding affinity. These simulations reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/35194049/Cooperative_multivalent_receptor_binding_promotes_exposure_of_the_SARS_CoV_2_fusion_machinery_core_ DB - PRIME DP - Unbound Medicine ER -