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    SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome

    Zimmerman, Maxwell I. and Porter, Justin R. and Ward, Michael D. and Singh, Sukrit and Vithani, Neha and Meller, Artur and Mallimadugula, Upasana L. and Kuhn, Catherine E. and Borowsky, Jonathan H. and Wiewiora, Rafal P. and Hurley, Matthew F. D. and Harbison, Aoife M and Fogarty, Carl A and Coffland, Joseph E. and Fadda, Elisa and Voelz, Vincent A. and Chodera, John D. and Bowman, Gregory R. (2020) SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome. bioRxiv.

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    SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression, and replication, which depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate an unprecedented 0.1 seconds of the viral proteome. Our simulations capture dramatic opening of the apo Spike complex, far beyond that seen experimentally, which explains and successfully predicts the existence of ‘cryptic’ epitopes. Different Spike homologues modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also observe dramatic conformational changes across the proteome, which reveal over 50 ‘cryptic’ pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.

    Item Type: Article
    Additional Information: Cite as: Zimmerman, M.I., Porter, J.R., Ward, M.D., Singh, S., Vithani, N., Meller, A., Mallimadugula, U.L., Kuhn, C.E., Borowsky, J.H., Wiewiora, R.P., Hurley, M.F.D., Harbison, A.M., Fogarty, C.A., Coffland, J.E., Fadda, E., Voelz, V.A., Chodera, J.D. & Bowman, G.R. 2020, SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome, Cold Spring Harbor Laboratory Press, Cold Spring Harbor.
    Keywords: Antiviral agents; Coronaviruses; COVID-19; Immune response; Pandemics; Proteomes; Severe acute respiratory syndrome coronavirus 2;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Faculty of Science and Engineering > Research Institutes > Hamilton Institute
    Faculty of Science and Engineering > Research Institutes > Human Health Institute
    Item ID: 17389
    Identification Number:
    Depositing User: Elisa Fadda
    Date Deposited: 06 Jul 2023 14:51
    Journal or Publication Title: bioRxiv
    Publisher: Cold Spring Harbor Laboratory Press
    Refereed: Yes
    Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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