Folding-based molecular simulations reveal mechanisms of the rotary motor F1–ATPase

摘要

Biomolecular machines fulfill their function through large conformational changes that typically occur on the millisecond time scale or longer. Conventional atomistic simulations can only reach microseconds at the moment. Here, extending the minimalist model developed for protein folding, we propose the “switching Gō model” and use it to simulate the rotary motion of ATP-driven molecular motor F1–ATPase. The simulation recovers the unidirectional 120° rotation of the γ-subunit, the rotor. The rotation was induced solely by steric repulsion from the α3β3 subunits, the stator, which undergoes conformation changes during ATP hydrolysis. In silico alanine mutagenesis further elucidated which residues play specific roles in the rotation. Finally, regarding the mechanochemical coupling scheme, we found that the tri-site model does not lead to successful rotation but that the always-bi-site model produces ≈30° and ≈90° substeps, perfectly in accord with experiments. In the always-bi-site model, the number of sites occupied by nucleotides is always two during the hydrolysis cycle. This study opens up an avenue of simulating functional dynamics of huge biomolecules that occur on the millisecond time scales involving large-amplitude conformational change.