Probing the Dynamic Structure-Function and Structure-Free Energy Relationships of the Coronavirus Main Protease with Biodynamics Theory.

ABSTRACT: The SARS-CoV-2 main protease (M^pro) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of apo and inhibitor-bound SARS-CoV/CoV-2 M^pro crystal structures, are underway in many laboratories. However, little is known about the dynamic enzyme mechanism, which is needed to inform both assay development and structure-based inhibitor design. Here, we apply biodynamics theory to characterize the structural dynamics of substrate-induced M^pro activation under nonequilibrium conditions. The catalytic cycle is governed by concerted dynamic structural rearrangements of domain 3 and the m-shaped loop (residues 132-147) on which Cys145 (comprising the thiolate nucleophile and half of the oxyanion hole) and

SUBMITTER: Wan H 

PROVIDER: S-EPMC7671103 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature