Statistical thermodynamics for functionally rotating mechanism of the multidrug efflux transporter AcrB.

AcrB, a homotrimer, is the pivotal part of a multidrug efflux pump. A "functionally rotating" picture has been proposed for the drug transport by AcrB, but its mechanism remains unresolved. Here, we investigate the energetics of the whole functional rotation cycle using our theoretical methods. We find that the packing efficiency of AcrB is ununiform, and this ununiformity plays imperative roles primarily through the solvent-entropy effect. When a proton binds to or dissociates from a protomer, the packing properties of this protomer and its two interfaces are perturbed overall in the direction that the solvent translational entropy is lowered. The packing properties of the other two protomers are then reorganized with the recovery or maintenance of closely packed interfaces, so that the solvent-entropy loss can be compensated. The functional structural change by an isolated protomer would cause a seriously large free-energy increase. By forming a trimer, any free-energy increase caused by a protomer is always canceled out by the free-energy decrease brought by the other two protomers via the mechanism mentioned above. The functional structural rotation is thus accomplished using the free-energy decrease arising from the transfer of only a single proton per cycle. The similarities to F1-ATPase are also discussed.