Rotation Mechanism of Molecular Motor V₁-ATPase Studied by Multiscale Molecular Dynamics Simulation

Enterococcus hirae V₁-ATPase is a molecular motor composed of the A₃B₃ hexamer ring and the central stalk. In association with ATP hydrolysis, three catalytic AB pairs in the A₃B₃ ring undergo conformational changes, which lead to a 120° rotation of the central stalk. To understand how the conformational changes of three catalytic pairs induce the 120° rotation of the central stalk, we performed multiscale molecular dynamics (MD) simulations in which coarse-grained and all-atom MD simulations were combined using a fluctuation matching methodology. During the rotation, a catalytic AB pair spontaneously adopted an intermediate conformation, which was not included in the initial inputs of the simulations and was essentially close to the "bindable-like" structure observed in a recently solved crystal structure. Furthermore, the creation of a space between the bindable-like and tight pairs was required for the central stalk to rotate without steric hindrance. These cooperative rearrangements of the three catalytic pairs are crucial for the rotation of the central stalk.