Molecular dynamics simulation of proton-transfer coupled rotations in ATP synthase F_O motor

The F_O motor in F_OF₁ ATP synthase rotates its rotor driven by the proton motive force. While earlier studies elucidated basic mechanisms therein, recent advances in high-resolution cryo-electron microscopy enabled to investigate proton-transfer coupled F_O rotary dynamics at structural details. Here, taking a hybrid Monte Carlo/molecular dynamics simulation method, we studied reversible dynamics of a yeast mitochondrial F_O. We obtained the 36°-stepwise rotations of F_O per one proton transfer in the ATP synthesis mode and the proton pumping in the ATP hydrolysis mode. In both modes, the most prominent path alternatively sampled states with two and three deprotonated glutamates in c-ring, by which the c-ring rotates one step. The free energy transduction efficiency in the model F_O motor reached ~ 90% in optimal conditions. Moreover, mutations in key glutamate and a highly conserved arginine increased proton leakage and markedly decreased the coupling, in harmony with previous experiments. This study provides a simple framework of simulations for chemical-reaction coupled molecular dynamics calling for further studies in ATP synthase and others.