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

31 December 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

COVID-19
spike
receptor binding domain (RBD)
allosteric
viral fusion
free energy landscape
SARS-CoV-2
coronavirus

Supplementary materials

Title
Description
Actions
Title
SARS-CoV-2 hinge free energy landscapes.SI
Description
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.