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Atomic-level characterization of the conformational transition pathways in SARS-CoV-1 and SARS-CoV-2 spike proteins

Dylan S Ogden, Mahmoud Moradi
doi: https://doi.org/10.1101/2022.11.29.518406
Dylan S Ogden
1Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, U.S.A.
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Mahmoud Moradi
1Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, U.S.A.
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  • For correspondence: moradi@uark.edu
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Abstract

Severe acute respiratory syndrome (SARS) coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) derive transmissibility from spike protein activation in the receptor binding domain (RBD) and binding to the host cell angiotensin converting enzyme 2 (ACE2). However, the mechanistic details that describe the large-scale conformational changes associated with spike protein activation or deactivation are still somewhat unknown. Here, we have employed an extensive set of nonequilibrium all-atom molecular dynamics (MD) simulations, utilizing a novel protocol, for the SARS-CoV-1 (CoV-1) and SARS-CoV-2 (CoV-2) prefusion spike proteins in order to characterize the conformational pathways associated with the active-to-inactive transition. Our results indicate that both CoV-1 and CoV-2 spike proteins undergo conformational transitions along pathways unique to each protein. We have identified a number of key residues that form various inter-domain saltbridges, suggesting a multi-stage conformational change along the pathways. We have also constructed the free energy profiles along the transition pathways for both CoV-1 and CoV-2 spike proteins. The CoV-2 spike protein must overcome larger free energy barriers to undergo conformational changes towards protein activation or deactivation, when compared to CoV-1.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 29, 2022.
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Atomic-level characterization of the conformational transition pathways in SARS-CoV-1 and SARS-CoV-2 spike proteins
Dylan S Ogden, Mahmoud Moradi
bioRxiv 2022.11.29.518406; doi: https://doi.org/10.1101/2022.11.29.518406
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Atomic-level characterization of the conformational transition pathways in SARS-CoV-1 and SARS-CoV-2 spike proteins
Dylan S Ogden, Mahmoud Moradi
bioRxiv 2022.11.29.518406; doi: https://doi.org/10.1101/2022.11.29.518406

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