Insights into the molecular mechanism of rotation in the Fo sector of ATP synthase

F1F0-ATP synthase is a ubiquitous membrane protein complex that efficiently converts a cell's transmembrane proton gradient into chemical energy stored as ATP. The protein is made of two molecular motors, F-0 and F-1, which are coupled by a central stalk. The membrane unit, F-0, converts the transmembrane electrochemical potential into mechanical rotation of a rotor in F-0 and the physically connected central stalk. Based on available data of individual components, we have built an all-atom model of F-0 and investigated through molecular dynamics simulations and mathematical modeling the mechanism of torque generation in F-0. The mechanism that emerged generates the torque at the interface of the a- and c-subunits of F-0 through side groups aSer-206, aArg-210, and aAsn-214 of the a-subunit and side groups cAsp-61 of the c-subunits. The mechanism couples protonation/deprotonation of two cAsp-61 side groups, juxtaposed to the a-subunit at any moment in time, to rotations of individual c-subunit helices as well as rotation of the entire c-subunit. The aArg-210 side group orients the cAsp-61 side groups and, thereby, establishes proton transfer via aSer-206 and aAsn-214 to proton half-channels, while preventing direct proton transfer between the half-channels. A mathematical model proves the feasibility of torque generation by the stated mechanism against loads typical during ATP synthesis; the essential model characteristics, e.g., helix and subunit rotation and associated friction constants, have been tested and furnished by steered molecular dynamics simulations.