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bioRxiv · 10.1101/2022.11.29.518406

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

Ogden, D. S.·Moradi, M.
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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.

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Ogden, D. S., Moradi, M.. 2022-11-29. Atomic-level characterization of the conformational transition pathways in SARS-CoV-1 and SARS-CoV-2 spike proteins. https://doi.org/10.1101/2022.11.29.518406

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