TY - JOUR
T1 - SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome
AU - Zimmerman, Maxwell I.
AU - Porter, Justin R.
AU - Ward, Michael D.
AU - Singh, Sukrit
AU - Vithani, Neha
AU - Meller, Artur
AU - Mallimadugula, Upasana L.
AU - Kuhn, Catherine E.
AU - Borowsky, Jonathan H.
AU - Wiewiora, Rafal P.
AU - Hurley, Matthew F.D.
AU - Harbison, Aoife M.
AU - Fogarty, Carl A.
AU - Coffland, Joseph E.
AU - Fadda, Elisa
AU - Voelz, Vincent A.
AU - Chodera, John D.
AU - Bowman, Gregory R.
N1 - Funding Information:
We are extremely grateful to all the citizen scientists who contributed their compute power to make this work possible and to members of the Folding@home community who volunteered to help with everything from technical support to translating content into multiple languages. Thanks to Microsoft AI for Health for helping us use Azure to run adaptive sampling simulations and to UKRI for providing computational resources to parallelize data analysis. Thanks to Pure Storage for providing a FlashBlade system to store our large datasets, to Seagate and Micron for additional storage and to MolSSI for helping organize public datasets. Thanks to Avast, AWS, Cisco, Linus Tech Tips, Microsoft Azure, Oracle and VMware for helping us to scale up Folding@home’s server-side infrastructure to keep up with the tremendous growth we experienced in such a short time. Thanks to AMD, ARM, Neocortix and Intel for helping to improve the performance of Folding@home on their hardware. Thanks to all of these companies for helping to spread the word about Folding@home and also to A16Z, Best Buy, CCP, CoreWeave, Daimler Truck AG, Dell, GitHub, HP, La Liga, Media Monks, Microcenter, NVIDIA and Telefonica. Thanks to CERN and the particle physics community for helping with data management and to DataDog for server monitoring services. Thanks to C. O. Barnes for providing the epitope contacts used for Fig. 2d. J.R.P. acknowledges support from F30HL146052. G.R.B. and his lab were supported by funding from Avast, the Center for the Science and Engineering of Living Systems (CSELS), an NSF RAPID award, NSF CAREER Award MCB-1552471, NIH R01 GM124007, NIH RF1 AG067194, a Burroughs Wellcome Fund Career Award at the Scientific Interface and a Packard Fellowship for Science and Engineering. J.D.C. acknowledges support from NIH grants P30 CA008748 and R01 GM121505. V.A.V. and M.F.D.H. acknowledge support from NIH grant R01 GM123296, NIH grant S10-OD020095 and NSF MRI grant CNS-1625061.
Funding Information:
J.D.C. is a current member of the scientific advisory board of OpenEye Scientific Software and a consultant to Foresite Laboratories. The Chodera laboratory receives or has received funding from multiple sources, including the National Institutes of Health, the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Relay Therapeutics, Entasis Therapeutics, Silicon Therapeutics, EMD Serono (Merck KGaA), AstraZeneca, Vir Biotechnology, Bayer, XtalPi, the Molecular Sciences Software Institute, the Starr Cancer Consortium, the Open Force Field Consortium, Cycle for Survival, a Louis V. Gerstner Young Investigator Award and the Sloan Kettering Institute. A complete funding history for the Chodera lab can be found at http://choderalab.org/funding.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/7
Y1 - 2021/7
N2 - 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.]
AB - 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.]
UR - http://www.scopus.com/inward/record.url?scp=85106243554&partnerID=8YFLogxK
U2 - 10.1038/s41557-021-00707-0
DO - 10.1038/s41557-021-00707-0
M3 - Article
C2 - 34031561
AN - SCOPUS:85106243554
VL - 13
SP - 651
EP - 659
JO - Nature Chemistry
JF - Nature Chemistry
SN - 1755-4330
IS - 7
ER -