Sequence Characterization and Molecular Modeling of Clinically Relevant Variants of the SARS-CoV‑2 Main Protease

The
SARS-CoV-2 main protease (Mpro)
is essential to viral replication and cleaves highly specific substrate
sequences, making it an obvious target for inhibitor design. However,
as for any virus, SARS-CoV-2 is subject to constant neutral drift
and selection pressure, with new Mpro mutations
arising over time. Identification and structural characterization
of Mpro variants is thus critical for
robust inhibitor design. Here we report sequence analysis, structure
predictions, and molecular modeling for seventy-nine Mpro variants, constituting all clinically observed
mutations in this protein as of April 29, 2020. Residue substitution
is widely distributed, with some tendency toward larger and more hydrophobic
residues. Modeling and protein structure network analysis suggest
differences in cohesion and active site flexibility, revealing patterns
in viral evolution that have relevance for drug discovery.