title: The Poulos-Kraut mechanism of Compound I formation in horseradish peroxidase: a QM/MM study.
abstract: QM/MM calculations are used to elucidate the Poulos-Kraut (Poulos, T. L.; Kraut, J. J. Biol. Chem. 1980, 255, 8199-8205) mechanism of O-O bond activation and Compound I (Cpd I) formation in HRP, in conditions corresponding to neutral to basic pH. Attempts to generate Compound I directly from the Fe(H2O2) complex by migrating the proton from the proximal oxygen to the distal one (1,2- proton shift) result in high barriers. The lowest energy mechanism was found to involve initial deprotonation of ferric hydrogen peroxide complex (involving spin crossover from the quartet to the doublet state) by His42 to form ferric-hydroperoxide (Cpd 0). Subsequently, the distal OH group of Cpd 0 is pulled by Arg38 and reprotonated by His42(H+) to form Cpd I and a water molecule that bridges the two residues. The structures of the intermediate and the transition state reveal the manner by which the Arg-His residues promote cooperatively the electronic reorganization that is required to attend the heterolytic O-O cleavage.
authors.affiliation: Department of Organic Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, Hebrew University of Jerusalem, Givat Ram Campus, 91904 Jerusalem, Israel.
authors.forename: Etienne
authors.initials: E
authors.lastname: Derat
authors.forename: Sason
authors.initials: S
authors.lastname: Shaik
mesh_terms: D005290:Ferric Compounds / Q000737:chemistry; D006735:Horseradish Peroxidase / Q000737:chemistry*; D006861:Hydrogen Peroxide / Q000737:chemistry; D008958:Models, Molecular; D011789:Quantum Theory; D012984:Software
chemical_list: D005290:Ferric Compounds; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase