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Free Energy Landscapes for RBD Opening in SARS-CoV-2 Spike Glycoprotein Simulations Suggest Key Interactions and a Potentially Druggable Allosteric Pocket

submitted on 30.12.2020, 12:25 and posted on 31.12.2020, 08:05 by Lucy Fallon, Kellon Belfon, Lauren Raguette, Yuzhang Wang, Christopher Corbo, Darya Stepanenko, Abbigayle Cuomo, Jose Guerra, Stephanie Budhan, Sarah Varghese, Robert Rizzo, Carlos Simmerling
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) an enveloped, positive-sense single-stranded RNA virus that is responsible for the COVID-19 pandemic. The viral spike is a class I viral fusion glycoprotein that extends from the viral surface and is responsible for viral entry into the host cell, and is the primary target of neutralizing antibodies. However, antibody recognition often involves variable surface epitopes on the spike, and the receptor binding domain (RBD) of the spike hides from immune recognition underneath a glycan shield aside from brief dynamic excursions to search for the host-cell surface receptor ACE2. Using an atomistic model of the glycosylated wild-type spike in the closed and 1-up RBD conformations, we identified specific interactions that stabilize the closed RBD, and mapped the free energy landscape for RBD opening. We characterized a transient pocket associated with a hinge motion during opening of the RBD, suggesting the possibility of allosteric control of the RBD via this region. Substitution of a conserved alanine to bulkier leucine in the pocket shifted the RBD equilibrium to favor the open, exposed state, as did removal of a conserved lysine that forms a critical salt-bridge in the closed, hidden state. Results from our virtual screening, MD simulations and free energy landscape calculations for wild-type spike suggest that small molecules can spontaneously bind to the highly conserved hinge pocket, and that such binding can shift the RBD equilibrium to favor the open state. Stabilizing the open state may facilitate antibody recognition by forcing the spike to expose critical RBD epitopes, and also could increase the likelihood of premature triggering of the spike fusion machinery via S1 shedding, neutralizing the infectious ability of the virus.


New Solvent Models, Sampling Methods and Maintenance of Amber Software

National Institute of General Medical Sciences

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Development, Validation, and Application of Structure-based Tools for Computational Molecular Design

National Institute of General Medical Sciences

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Research Corporation for Science Advancement COVID Initiative grant #27350

DOE Office of Science through the National Virtual Biotechnology Laboratory


Email Address of Submitting Author


Stony Brook University


United States

ORCID For Submitting Author


Declaration of Conflict of Interest