Cavity hydration dynamics in cytochrome c oxidase and functional implications

Significance Cytochrome c oxidase (CcO) reduces molecular oxygen to generate the proton motive force across the membrane that drives ATP synthesis. Internal water molecules in and near a central cavity play important roles in mediating the proton transfers. Molecular simulations of CcO reveal reversible transitions between wet and dry configurations of this internal cavity in response to the charge state of key cofactors and residues. Quantitative analysis of the free energy change and timescale of the transition suggests that hydration-level change of the central cavity is an essential feature that contributes to the vectorial efficiency of proton pumping in CcO. Thus, wetting transition of protein internal cavities can be functionally significant, especially for the transport of charged species.