SAM1 semiempirical calculations on the mechanism of cytochrome P450 metabolism

We present modeling results on the metabolism of alkanes by cytochrome P450 using the semiempirical method SAM1. For our model system consisting of unsubstituted porphyrin, iron, and methylthiolate, the structures for the complexes in all possible spin-states throughout the reaction cycle were calculated and extensive conformational searches were performed. These enable us to discuss the changes in relative energies, atomic charges and structures for each reaction step. The reaction cascade is exothermic for all steps except the last, the substrate oxidation, which has been suggested to be rate-limiting from experimental evidence. The oxygen-oxygen bond is elongated step-by-step and the atomic charge on the iron-bound oxygen analogously reduced. The porphyrin nitrogens act as a charge buffer, whereas iron becomes progressively more positive. Dioxygen is transformed to the singlet by end-on coordination to iron(II). The addition of two protons gives a concerted dissociation of water instead of the unfavorable water-oxide-complex. Thus, our results are in full agreement with experimental data and support the accepted mode of action of P450 enzymes. (C) 2001 Elsevier Science B.V. All rights reserved.