SARS-CoV‑2 Main Protease: A Molecular Dynamics Study

Herein, we investigate the structure
and flexibility of the hydrated
SARS-CoV-2 main protease by means of 2.0 μs molecular dynamics
(MD) simulations in explicit solvent. After having performed electrostatic
pKa calculations on several X-ray structures,
we consider both the native (unbound) configuration of the enzyme
and its noncovalent complex with a model peptide, Ace-Ala-Val-Leu-Gln∼Ser-Nme,
which mimics the polyprotein sequence recognized at the active site.
For each configuration, we also study their monomeric and homodimeric
forms. The simulations of the unbound systems show that the relative
orientation of domain III is not stable in the monomeric form and
provide further details about interdomain motions, protomer–protomer
interactions, inter-residue contacts, accessibility at the catalytic
site, etc. In the presence of the peptide substrate, the monomeric
protease exhibits a stable interdomain arrangement, but the relative
orientation between the scissile peptide bond and the catalytic dyad
is not favorable for catalysis. By means of comparative analysis,
we further assess the catalytic impact of the enzyme dimerization,
the actual flexibility of the active site region, and other structural
effects induced by substrate binding. Overall, our computational results
complement previous crystallographic studies on the SARS-CoV-2 enzyme
and, together with other simulation studies, should contribute to
outline useful structure–activity relationships.