Free Energy Landscapes from SARS-CoV‑2 Spike Glycoprotein Simulations Suggest that RBD Opening Can Be Modulated via Interactions in an Allosteric Pocket

The SARS-CoV-2 coronavirus is an
enveloped, positive-sense single-stranded
RNA virus that is responsible for the COVID-19 pandemic. The 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. The receptor binding
domain (RBD) of the spike samples multiple conformations in a compromise
between evading immune recognition and searching for the host-cell
surface receptor. Using atomistic simulations of the glycosylated
wild-type spike in the closed and 1-up RBD conformations, we map the
free energy landscape for RBD opening and identify interactions in
an allosteric pocket that influence RBD dynamics. The results provide
an explanation for experimental observation of increased antibody
binding for a clinical variant with a substitution in this pocket.
Our results also suggest the possibility of allosteric targeting of
the RBD equilibrium to favor open states via binding of small molecules
to the hinge pocket. In addition to potential value as experimental
probes to quantify RBD conformational heterogeneity, small molecules
that modulate the RBD equilibrium could help explore the relationship
between RBD opening and S1 shedding.