Computational and Experimental Study of the Conformational Variation of the Catalytic Residue His41 of the SARS-CoV-2 Main Protease.

ABSTRACT: The main protease (M^pro) is essential for the replication of SARS-CoV-2, making it one of the major therapeutic targets for COVID-19 treatment. Here, we explored the conformational dynamics and energetics of the catalytic residue His41 in M^pro, as revealed by a rare conformational shift observed in the cocrystal structures of M^pro bound by certain inhibitors. Using steered molecular dynamics combined with umbrella sampling, we demonstrated that π-cation interactions between these inhibitors and the ionized catalytic dyad significantly reduced the energy barrier for the conformational flip of the His41 side chain. To further investigate the structure-activity relationship linked to this conformational change, we designed and synthesized a series of covalent

SUBMITTER: Zhou J 

PROVIDER: S-EPMC12413198 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature