Combined DFT and electrostatic calculations of pK a s in proteins: study of 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 indicate that one of the histidine ligands of the enzyme’s Cu B center, His291, may play the role of the pumping element. In this paper, we review the first principles calculations that are used to study models of the catalytic center of CcO, and calculate the pK a of the His291 residue for both the reduced and oxidized states of the catalytic center of the enzyme. We also review the structure and function of CcO, describe the proposed mechanism of proton pumping, and identify the key problems that can be addressed computationally in this area and describe the methods for their solution. The outstanding theoretical and computational challenges of the area are also discussed.