The cytochrome P450 enzymes catalyze the hydroxylation of organic substrates by dioxygen. The high-potential reactive intermediate in cytochrome P450 catalysis, compound I (CI), has the capacity to deliver oxidizing equivalents (holes) to the side chains of tryptophan, tyrosine, and cysteine amino acids. Successful P450 catalysis requires that CI reacts more rapidly with a substrate than with these redox-active residues. The kinetics of hole transfer to tryptophan, tyrosine, and cysteine residues in four different P450 enzymes have been modeled using X-ray crystal structure coordinates and the semiclassical theory of electron transfer. Monte Carlo sampling of reaction driving forces has been used to account for uncertainties in the formal potentials of redox-active groups. The kinetics simulations suggest that the mean survival lifetimes of holes on the hemes range from ~100 ns to ~100 μs. Although hole transfer to the enzyme surface through redox-active amino acid reduces substrate oxidation efficiency, it can protect the enzyme from damage when reaction with substrate fails.
