Theory of chemical bonds in metalloenzymes. VII. Hybrid‐density functional theory studies on the electronic structures of P450

A first principle investigation has been carried out for intermediate states of the catalytic cycle of a cytochrome P450. To elucidate the whole catalytic cycle of P450, the electronic and geometrical structures are investigated not only at each ground state but also at low‐lying energy levels. Using the natural orbital analysis, the nature of chemical bonds and magnetic interactions are investigated. The ground state of the Compound 1 ( cpd1 ) is calculated to be a doublet state, which is generated by the antiferromagnetic coupling between a triplet Fe(IV)?O moiety and a doublet ligand radical. We found that an excited doublet state of the cpd1 is composed of a singlet Fe(IV)?O and a doublet ligand radical. This excited state lies 20.8 kcal mol^?1 above the ground spin state, which is a non‐negligible energy level as compared with the activation energy barrier of ΔE^# = 26.6 kcal mol^?1. The reaction path of the ground state of cpd1 is investigated on the basis of the model reaction: ³O(³p) + CH₄. The computational results suggest that the reactions of P450 at the ground and excited states proceed through abstraction (³O‐model) and insertion (¹O‐model) mechanisms, respectively. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008