Electron transfer pathways in cytochrome c oxidase

Abstract

Mixed quantum mechanical/molecular mechanics calculations were used to explore the electron pathway of the terminal electron transfer enzyme, cytochrome c oxidase. This enzyme catalyzes the reduction of molecular oxygen to water in a multiple step process. Density functional calculations on the three redox centers allowed for the characterization of the electron transfer mechanism, following the sequence Cu A → heme a → heme a 3. This process is largely affected by the presence of positive charges, confirming the possibility of a proton coupled electron transfer. An extensive mapping of all residues involved in the electron transfer, between the Cu A center (donor) and the O 2 reduction site heme a 3-Cu B (receptor), was obtained by selectively activating/deactivating different quantum regions. The method employed, called QM/MM e-pathway, allowed the identification of key residues along the possible electron transfer paths, consistent with experimental data. In particular, the role of arginines 481 and 482 appears crucial in the Cu A → heme a and in the heme a → heme a 3 electron transfer processes. This article is part of a Special Issue entitled: Allosteric cooperativity in respiratory proteins.