Combined Density Functional Theory (DFT) and Electrostatics Study of the Proton Pumping Mechanism in Cytochrome C Oxidase

Cytochrome c oxidase is a redox-driven proton pump which converts atmospheric oxygen to water and couples the oxygen reduction reaction to the creation of a membrane proton gradient. The structure of the enzyme has been solved; however, the mechanism of proton pumping is still poorly understood. Recent calculations from this group indicate that one of the histidine ligands of the enzyme's CuB center, His291, may play the role of the pumping element. Here, we discuss results of calculations that combined first principles density functional theory (DFT) and continuum electrostatics to evaluate the energetics of the key energy generating step—the transfer of the chemical proton to the binuclear center of the enzyme, where the hydroxyl group is converted to water, and the concerted expulsion of the proton from d-nitrogen of the His291 ligand of the CuB center. Keywords: cytochrome c oxidase; electron transfer; proton transfer; coupled electron and proton transfer reactions; DFT continuum electrostatics; DFT/electrostatic calculation; proton pumping; redox-coupled pKa; pKa calculation