title: New features in the catalytic cycle of cytochrome P450 during the formation of compound I from compound 0.
abstract: Density functional theory (DFT) is applied to the dark section of the catalytic cycle of the enzyme cytochrome P450, namely, the formation of the active species, Compound I (Cpd I), from the ferric-hydroperoxide species (Cpd 0) by a protonation-assisted mechanism. The chosen 96-atom model includes the key functionalities deduced from experiment: Asp(251), Thr(252), Glu(366), and the water channels that relay the protons. The DFT model calculations show that (a) Cpd I is not formed spontaneously from Cpd 0 by direct protonation, nor is the process very exothermic. The process is virtually thermoneutral and involves a significant barrier such that formation of Cpd I is not facile on this route. (b) Along the protonation pathway, there exists an intermediate, a protonated Cpd 0, which is a potent oxidant since it is a ferric complex of water oxide. Preliminary quantum mechanical/molecular mechanical calculations confirm that Cpd 0 and Cpd I are of similar energy for the chosen model and that protonated Cpd 0 may exist as an unstable intermediate. The paper also addresses the essential role of Thr(252) as a hydrogen-bond acceptor (in accord with mutation studies of the OH group to OMe).
authors.affiliation: Department of Organic Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
authors.forename: Devesh
authors.initials: D
authors.lastname: Kumar
authors.forename: Hajime
authors.initials: H
authors.lastname: Hirao
authors.forename: Sam P
authors.initials: SP
authors.lastname: de Visser
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: D000596:Amino Acids / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D005290:Ferric Compounds / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D011522:Protons; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D000596:Amino Acids; D005290:Ferric Compounds; D011522:Protons; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide