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SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome.

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.

SUBMITTER: Zimmerman MI

PROVIDER: S-EPMC8249329 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome.

Zimmerman Maxwell I MI Porter Justin R JR Ward Michael D MD Singh Sukrit S Vithani Neha N Meller Artur A Mallimadugula Upasana L UL Kuhn Catherine E CE Borowsky Jonathan H JH Wiewiora Rafal P RP Hurley Matthew F D MFD Harbison Aoife M AM Fogarty Carl A CA Coffland Joseph E JE Fadda Elisa E Voelz Vincent A VA Chodera John D JD Bowman Gregory R GR

Nature chemistry 20210524 7

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 proteom ...[more]

PMID: 34031561

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Project description:Proteins are dynamic molecules that undergo conformational changes to a broad spectrum of different excited states. Unfortunately, the small populations of these states make it difficult to determine their structures or functional implications. Computer simulations are an increasingly powerful means to identify and characterize functionally relevant excited states. However, this advance has uncovered a further challenge: it can be extremely difficult to identify the most salient features of large simulation data sets. We reasoned that many functionally relevant conformational changes are likely to involve large, cooperative changes to the surfaces that are available to interact with potential binding partners. To examine this hypothesis, we introduce a method that returns a prioritized list of potentially functional conformational changes by segmenting protein structures into clusters of residues that undergo cooperative changes in their solvent exposure, along with the hierarchy of interactions between these groups. We term these groups exposons to distinguish them from other types of clusters that arise in this analysis and others. We demonstrate, using three different model systems, that this method identifies experimentally validated and functionally relevant conformational changes, including conformational switches, allosteric coupling, and cryptic pockets. Our results suggest that key functional sites are hubs in the network of exposons. As a further test of the predictive power of this approach, we apply it to discover cryptic allosteric sites in two different ?-lactamase enzymes that are widespread sources of antibiotic resistance. Experimental tests confirm our predictions for both systems. Importantly, we provide the first evidence, to our knowledge, for a cryptic allosteric site in CTX-M-9 ?-lactamase. Experimentally testing this prediction did not require any mutations and revealed that this site exerts the most potent allosteric control over activity of any pockets found in ?-lactamases to date. Discovery of a similar pocket that was previously overlooked in the well-studied TEM-1 ?-lactamase demonstrates the utility of exposons.

Dataset Information

SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome.

Publications

SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome.

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