A Minimal Chemo-mechanical Markov Model for Rotary Catalysis of F1-ATPase

F1-ATPase, the catalytic domain of ATP synthase, is pivotal for mechanochemical energy conversion in mitochondria. Aiming at a minimal yet quantitative and thermodynamically consistent model for its rotary catalysis mechanism, here we developed a chemo-mechanical Markov model incorporating essential conformational and chemical degrees of freedom. By systematically evaluating over 14,000 model variants via Bayesian inference and cross-validation, we find that a fully functional minimal model requires four functionally distinct {beta}-subunit conformations. Our model reconciles the decade-long bi-site versus tri-site controversy, showing that both pathways contribute depending on ATP concentration. Furthermore, our model suggests a Brownian-ratchet-like mechanism that explains the observation that one ATP hydrolysis event can trigger larger than 120{degrees} rotations, thereby explaining seemingly over 100% efficiency. Beyond this prototypic example of a complex biomolecular machine, our approach should enable one to study other enzymatic mechanisms that implement close coupling between conformational motions, substrate binding, and chemical reactions.