SARS-CoV-2 simulations go exascale to predict dramatic spike opening and 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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)651-659
Number of pages9
JournalNature Chemistry
Volume13
Issue number7
DOIs
StatePublished - Jul 2021

Fingerprint

Dive into the research topics of 'SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome'. Together they form a unique fingerprint.

Cite this