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

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 G (o) over bar model" and use it to simulate the rotary motion of ATP-driven molecular motor F-1-ATPase. The simulation recovers the unidirectional 120 degrees rotation of the gamma-subunit, the rotor. The rotation was induced solely by steric repulsion from the alpha(3)beta(3) subunits, the stator, which undergoes conformation changes during ATIP 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 approximate to 30 degrees and approximate to 90 degrees 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.