Cargando…

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

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 t...

Descripción completa

Detalles Bibliográficos
Autores principales: Zimmerman, Maxwell I., Porter, Justin R., Ward, Michael D., Singh, Sukrit, Vithani, Neha, Meller, Artur, Mallimadugula, Upasana L., Kuhn, Catherine E., Borowsky, Jonathan H., Wiewiora, Rafal P., Hurley, Matthew F. D., Harbison, Aoife M, Fogarty, Carl A, Coffland, Joseph E., Fadda, Elisa, Voelz, Vincent A., Chodera, John D., Bowman, Gregory R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249329/
https://www.ncbi.nlm.nih.gov/pubmed/34031561
http://dx.doi.org/10.1038/s41557-021-00707-0
_version_ 1783716887505403904
author Zimmerman, Maxwell I.
Porter, Justin R.
Ward, Michael D.
Singh, Sukrit
Vithani, Neha
Meller, Artur
Mallimadugula, Upasana L.
Kuhn, Catherine E.
Borowsky, Jonathan H.
Wiewiora, Rafal P.
Hurley, Matthew F. D.
Harbison, Aoife M
Fogarty, Carl A
Coffland, Joseph E.
Fadda, Elisa
Voelz, Vincent A.
Chodera, John D.
Bowman, Gregory R.
author_facet Zimmerman, Maxwell I.
Porter, Justin R.
Ward, Michael D.
Singh, Sukrit
Vithani, Neha
Meller, Artur
Mallimadugula, Upasana L.
Kuhn, Catherine E.
Borowsky, Jonathan H.
Wiewiora, Rafal P.
Hurley, Matthew F. D.
Harbison, Aoife M
Fogarty, Carl A
Coffland, Joseph E.
Fadda, Elisa
Voelz, Vincent A.
Chodera, John D.
Bowman, Gregory R.
author_sort Zimmerman, Maxwell I.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8249329
institution National Center for Biotechnology Information
language English
publishDate 2021
record_format MEDLINE/PubMed
spelling pubmed-82493292021-07-02 SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome Zimmerman, Maxwell I. Porter, Justin R. Ward, Michael D. Singh, Sukrit Vithani, Neha Meller, Artur Mallimadugula, Upasana L. Kuhn, Catherine E. Borowsky, Jonathan H. Wiewiora, Rafal P. Hurley, Matthew F. D. Harbison, Aoife M Fogarty, Carl A Coffland, Joseph E. Fadda, Elisa Voelz, Vincent A. Chodera, John D. Bowman, Gregory R. Nat Chem Article 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. 2021-05-24 2021-07 /pmc/articles/PMC8249329/ /pubmed/34031561 http://dx.doi.org/10.1038/s41557-021-00707-0 Text en https://creativecommons.org/licenses/by/4.0/It is made available under a CC-BY 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zimmerman, Maxwell I.
Porter, Justin R.
Ward, Michael D.
Singh, Sukrit
Vithani, Neha
Meller, Artur
Mallimadugula, Upasana L.
Kuhn, Catherine E.
Borowsky, Jonathan H.
Wiewiora, Rafal P.
Hurley, Matthew F. D.
Harbison, Aoife M
Fogarty, Carl A
Coffland, Joseph E.
Fadda, Elisa
Voelz, Vincent A.
Chodera, John D.
Bowman, Gregory R.
SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome
title SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome
title_full SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome
title_fullStr SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome
title_full_unstemmed SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome
title_short SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome
title_sort sars-cov-2 simulations go exascale to capture spike opening and reveal cryptic pockets across the proteome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249329/
https://www.ncbi.nlm.nih.gov/pubmed/34031561
http://dx.doi.org/10.1038/s41557-021-00707-0
work_keys_str_mv AT zimmermanmaxwelli sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT porterjustinr sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT wardmichaeld sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT singhsukrit sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT vithanineha sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT mellerartur sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT mallimadugulaupasanal sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT kuhncatherinee sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT borowskyjonathanh sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT wiewiorarafalp sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT hurleymatthewfd sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT harbisonaoifem sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT fogartycarla sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT cofflandjosephe sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT faddaelisa sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT voelzvincenta sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT choderajohnd sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome
AT bowmangregoryr sarscov2simulationsgoexascaletocapturespikeopeningandrevealcrypticpocketsacrosstheproteome