Reactivity patterns of protonated Compound II and Compound I of Cytochrome P450: What is the better oxidant?

The cytochromes P450 are versatile enzymes in human physiology that perform substrate hydroxylation reactions extremely efficient. In this work, we present results of a computational study on the reactivity patterns of Compound I, Compound II and protonated Compound II with model substrates and addresses the question, which of those is the most effective oxidant. All calculations, regardless of the substrate, implicate that Compound I is the superior oxidant of the three. However, Compound II and protonated Compound II are found to react with free energies of activation that are only a few kcal mol-1 higher in energy than those obtained with Compound I. Therefore, Compound II and protonated Compound II should be able to react with aliphatic groups with moderate C-H bond strengths. We have analyzed all results in detail and give electronic, thermochemical, valence bond and molecular orbital rationalizations on the reactivity differences and explain experimental product distributions. Overall, the work implies that alternative oxidants could operate alongside Compound I in complex reaction mechanisms of enzymatic and synthetic iron porphyrin complexes.