Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches.

ABSTRACT: Papain-like protease (PL^pro) is a promising therapeutic target against SARS-CoV-2, but its restricted S1/S2 subsites pose an obstacle in developing active site-directed inhibitors. We have recently identified C270 as a novel covalent allosteric site for SARS-CoV-2 PL^pro inhibitors. Here we present a theoretical investigation of the proteolysis reaction catalyzed by the wild-type SARS-CoV-2 PL^pro as well as the C270R mutant. Enhanced sampling MD simulations were first performed to explore the influence of C270R mutation on the protease dynamics, and sampled thermodynamically favorable conformations were then submitted to MM/PBSA and QM/MM MD simulations for thorough characterization of the protease-substrate binding and covalent reactions. The disclosed prot

SUBMITTER: Shao Q 

PROVIDER: S-EPMC10171076 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature