Quantum chemistry applied to the mechanisms of transition metal containing enzymes -- cytochrome c oxidase, a particularly challenging case.

The Density functional theory (B3LYP) has been used to study the mechanisms of O--O bond cleavage and proton pumping in cytochrome c oxidase. To understand how the energy from the exergonic reduction of molecular oxygen is used to pump protons across the mitochondrial membrane, the energetics of all steps in the catalytic cycle have to be evaluated. For this purpose, models have to be designed that can accurately reproduce relative redox potentials and pKa values within the active site. The present study shows that it is possible to construct such models and to calculate energy profiles which, to a large extent, agree with experimental information. However, the energy profiles point out a problem with an unbalanced partitioning of the energy between the reductive and oxidative half cycles, which is in disagreement with the experimental observation that the proton pumping is evenly distributed between the two half cycles. A conclusion from the present study is, therefore, that something is probably still missing in the modeling of the active site.