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