Normal-mode-based modeling of allosteric couplings that underlie cyclic conformational transition in F(1) ATPase.

F(1) ATPase, a rotary motor comprised of a central stalk (gamma subunit) enclosed by three alpha and beta subunits alternately arranged in a hexamer, features highly cooperative binding and hydrolysis of ATP. Despite steady progress in biophysical, biochemical, and computational studies of this fascinating motor, the structural basis for cooperative ATPase involving its three catalytic sites remains not fully understood. To illuminate this key mechanistic puzzle, we have employed a coarse-grained elastic network model to probe the allosteric couplings underlying the cyclic conformational transition in F(1) ATPase at a residue level of detail. We will elucidate how ATP binding and product (ADP and phosphate) release at two catalytic sites are coupled with the rotation of gamma subunit via various domain motions in alpha(3)beta(3) hexamer (including intrasubunit hinge-bending motions in beta subunits and intersubunit rigid-body rotations between adjacent alpha and beta subunits). To this end, we have used a normal-mode-based correlation analysis to quantify the allosteric couplings of these domain motions to local motions at catalytic sites and the rotation of gamma subunit. We have then identified key amino acid residues involved in the above couplings, some of which have been validated against past studies of mutated and gamma-truncated F(1) ATPase. Our finding strongly supports a binding change mechanism where ATP binding to the empty catalytic site triggers a series of intra- and intersubunit domain motions leading to ATP hydrolysis and product release at the other two closed catalytic sites.