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

Maxwell I. Zimmerman, Justin R. Porter, Michael D. Ward, Sukrit Singh, Neha Vithani, Artur Meller, Upasana L. Mallimadugula, Catherine E. Kuhn, Jonathan H. Borowsky, View ORCID ProfileRafal P. Wiewiora, Matthew F. D. Hurley, Aoife M Harbison, Carl A Fogarty, Joseph E. Coffland, Elisa Fadda, Vincent A. Voelz, View ORCID ProfileJohn D. Chodera, Gregory R. Bowman
doi: https://doi.org/10.1101/2020.06.27.175430
Maxwell I. Zimmerman
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Justin R. Porter
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Michael D. Ward
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Sukrit Singh
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Neha Vithani
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Artur Meller
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Upasana L. Mallimadugula
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Catherine E. Kuhn
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Jonathan H. Borowsky
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Rafal P. Wiewiora
3Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
4Computational and Systems Biology Program, Sloan Kettering Institute, New York, New York 10065, United States
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Matthew F. D. Hurley
5Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
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Aoife M Harbison
6Department of Chemistry and Hamilton Institute, Maynooth University, Maynooth, Kildare, Ireland
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Carl A Fogarty
6Department of Chemistry and Hamilton Institute, Maynooth University, Maynooth, Kildare, Ireland
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Joseph E. Coffland
7Cauldron Development LLC
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Elisa Fadda
6Department of Chemistry and Hamilton Institute, Maynooth University, Maynooth, Kildare, Ireland
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Vincent A. Voelz
5Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
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John D. Chodera
4Computational and Systems Biology Program, Sloan Kettering Institute, New York, New York 10065, United States
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Gregory R. Bowman
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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  • For correspondence: g.bowman@wustl.edu
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Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 07, 2020.
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SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome
Maxwell I. Zimmerman, Justin R. Porter, Michael D. Ward, Sukrit Singh, Neha Vithani, Artur Meller, Upasana L. Mallimadugula, Catherine E. Kuhn, Jonathan H. Borowsky, Rafal P. Wiewiora, Matthew F. D. Hurley, Aoife M Harbison, Carl A Fogarty, Joseph E. Coffland, Elisa Fadda, Vincent A. Voelz, John D. Chodera, Gregory R. Bowman
bioRxiv 2020.06.27.175430; doi: https://doi.org/10.1101/2020.06.27.175430
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SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome
Maxwell I. Zimmerman, Justin R. Porter, Michael D. Ward, Sukrit Singh, Neha Vithani, Artur Meller, Upasana L. Mallimadugula, Catherine E. Kuhn, Jonathan H. Borowsky, Rafal P. Wiewiora, Matthew F. D. Hurley, Aoife M Harbison, Carl A Fogarty, Joseph E. Coffland, Elisa Fadda, Vincent A. Voelz, John D. Chodera, Gregory R. Bowman
bioRxiv 2020.06.27.175430; doi: https://doi.org/10.1101/2020.06.27.175430

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