SARS-CoV-2 is the coronavirus that is responsible for the COVID-19 pandemic. Each virion has ~ 25 spike glycoproteins extended from the surface; these are responsible for entry of a coronavirus into the host cell and are the primary target of immune response. Cryo-EM studies have generated a large number of structures for the spike, either alone or bound to ACE2 or antibodies, with the three receptor binding domains (RBDs) seen closed, open, or in various combinations. Binding to ACE2 requires the RBD to be open, and is believed to trigger a series of dramatic conformational changes in the spike that lead to the shedding of the S1 subunit and transition to the experimentally observed post-fusion structure for the S2 subunit. The exact order of events is poorly understood due to lack of experimental structural data for intermediate states. Here, we present all-atom simulations, guided by analysis of ~ 100 existing experimental structures, that suggest a model for the structural and energetic coupling between the dual roles of the spike: receptor binding and cell fusion. A deeper understanding of the events that trigger viral membrane fusion may facilitate development of mechanism-based strategies to prematurely inactive the spike.

What happens after ACE2 binds? Modeling the coronavirus spike conformational changes that lead to membrane fusion

ACS Fall 2021

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