Molecular Mechanism of ATP Hydrolysis Catalyzed by p97: A QM/MM Study.

ABSTRACT: A computational study of p97/VCP ATPase using hybrid quantum mechanics/molecular mechanics (QM/MM) simulations is presented that explores the conformational landscape of the active site and hydrolysis-competent states of the crystallographic water molecules. Our investigation focuses on the reaction mechanism, particularly the events of the rate-determining first reaction step, which we study using extensive sampling with the path well-tempered metadynamics extended-system adaptive biasing force (WTM-eABF) enhanced sampling method. We identify the highly conserved glutamate (Glu305) from the Walker B motif as a catalytic base that activates the lytic water molecule for nucleophilic attack on the γ-phosphate in the first reaction step, while the final product is formed in a second step that

SUBMITTER: Szanto JK 

PROVIDER: S-EPMC12529919 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature