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Zimmerman MI , Porter JR , Ward MD , Singh S , Vithani N , Meller A , Mallimadugula UL , Kuhn CE , Borowsky JH , Wiewiora RP , Hurley MFD , Harbison AM , Fogarty CA , Coffland JE , Fadda E , Voelz VA , Chodera JD , Bowman GR
SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome
Nat Chem. 2021 May 24;13(7) :651-659
PMID: 34031561    PMCID: PMC8249329    URL: https://www.ncbi.nlm.nih.gov/pubmed/34031561
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Abstract
SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression and replication that 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 0.1 seconds of the viral proteome. Our adaptive sampling simulations predict dramatic opening of the apo spike complex, far beyond that seen experimentally, explaining and predicting the existence of 'cryptic' epitopes. Different spike variants modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also discover 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.
Notes
1755-4349 Zimmerman, Maxwell I Porter, Justin R Orcid: 0000-0002-0340-951x Ward, Michael D Singh, Sukrit Orcid: 0000-0003-1914-4955 Vithani, Neha Meller, Artur Mallimadugula, Upasana L Kuhn, Catherine E Borowsky, Jonathan H Orcid: 0000-0002-0761-3585 Wiewiora, Rafal P Hurley, Matthew F D Harbison, Aoife M Fogarty, Carl A Orcid: 0000-0001-5333-8206 Coffland, Joseph E Fadda, Elisa Voelz, Vincent A Chodera, John D Orcid: 0000-0003-0542-119x Bowman, Gregory R Orcid: 0000-0002-2083-4892 Journal Article England Nat Chem. 2021 May 24. doi: 10.1038/s41557-021-00707-0.