title: QM/MM study of mechanisms for compound I formation in the catalytic cycle of cytochrome P450cam.
abstract: In the catalytic cycle of cytochrome P450cam, after molecular oxygen binds as a ligand to the heme iron atom to yield a ferrous dioxygen complex, there are fast proton transfers that lead to the formation of the active species, Compound I (Cpd I), which are not well understood because they occur so rapidly. In the present work, the conversion of the ferric hydroperoxo complex (Cpd 0) to Cpd I has been investigated by combined quantum-mechanical/molecular-mechanical (QM/MM) calculations. The residues Asp(251) and Glu(366) are considered as proton sources. In mechanism I, a proton is transported to the distal oxygen atom of the hydroperoxo group via a hydrogen bonding network to form protonated Cpd 0 (prot-Cpd0: FeOOH(2)), followed by heterolytic O-O bond cleavage that generates Cpd I and water. Although a local minimum is found for prot-Cpd0 in the Glu(366) channel, it is very high in energy (more than 20 kcal/mol above Cpd 0) and the barriers for its decay are only 3-4 kcal/mol (both toward Cpd 0 and Cpd I). In mechanism II, an initial O-O bond cleavage followed by a concomitant proton and electron transfer yields Cpd I and water. The rate-limiting step in mechanism II is O-O cleavage with a barrier of about 13-14 kcal/mol. According to the QM/MM calculations, the favored low-energy pathway to Cpd I is provided by mechanism II in the Asp(251) channel. Cpd 0 and Cpd I are of similar energies, with a slight preference for Cpd I.
authors.affiliation: Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zheng
authors.forename: Dongqi
authors.initials: D
authors.lastname: Wang
authors.forename: Walter
authors.initials: W
authors.lastname: Thiel
authors.forename: Sason
authors.initials: S
authors.lastname: Shaik
mesh_terms: D019475:Camphor 5-Monooxygenase / Q000737:chemistry* / Q000378:metabolism*; D002384:Catalysis; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011487:Protein Conformation; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D019475:Camphor 5-Monooxygenase