Electron transfer pathways in cytochrome c oxidase

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 CuA → heme a → heme a3. 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 CuA center (donor) and the O2 reduction site heme a3-CuB (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 CuA → heme a and in the heme a → heme a3 electron transfer processes. This article is part of a Special Issue entitled: Allosteric cooperativity in respiratory proteins.

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► Cytochrome c oxidase electron transfer pathways studied by a QM/MM approach.
► Key residues for electron transfer identified.
► Plasticity for electron flow regulated by the neighboring arginines 481 and 482.
► Two step ET process following the CuA -> heme a -> heme a3 sequence.