The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind, fuse, and enter cells are important to understand from both fundamental and therapeutic perspectives. Spike proteins are trimeric with each protomer consisting of two domains: S1, which contains the angiotensin-converting enzyme 2 (ACE2) receptor binding domain, and S2, which contains the viral fusion machinery. Ostensibly, the binding of spike trimers to ACE2 receptors promotes the preparation of the fusion machinery by dissociation of the S1 domains. In this talk, we describe our recent development of data-driven and rapidly-deployable coarse-grained models of spike and ACE2 glycoproteins. We investigate the dynamical mechanisms involved in viral binding and exposure of the S2 trimeric core using coarse-grained molecular dynamics simulations. We show that spike trimers cooperatively bind to multiple ACE2 dimers. The multivalent interaction cyclically and processively induces S1 dissociation, thereby exposing the S2 core containing the fusion machinery. Our simulations reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry. Finally, we discuss how our coarse-graining strategy can be improved upon and adapted for future infectious disease outbreaks.

Investigating cooperative SARS-CoV-2 spike protein and ACE2 receptor binding using coarse-grained modeling and simulation

ACS Fall 2021

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