title: Quantum mechanical/molecular mechanical study on the mechanisms of compound I formation in the catalytic cycle of chloroperoxidase: an overview on heme enzymes.
abstract: The formation of Compound I (Cpd I), the active species of the enzyme chloroperoxidase (CPO), was studied using QM/MM calculation. Starting from the substrate complex with hydrogen peroxide, FeIII-HOOH, we examined two alternative mechanisms on the three lowest spin-state surfaces. The calculations showed that the preferred pathway involves heterolytic O-O cleavage that proceeds via the iron hydroperoxide species, i.e., Compound 0 (Cpd 0), on the doublet-state surface. This process is effectively concerted, with a barrier of 12.4 kcal/mol, and is catalyzed by protonation of the distal OH group of Cpd 0. By comparison, the path that involves a direct O-O cleavage from FeIII-HOOH is less favored. A proton coupled electron transfer (PCET) feature was found to play an important role in the mechanism nascent from Cpd 0. Initially, the O-O cleavage progresses in a homolytic sense, but as soon as the proton is transferred to the distal OH, it triggers an electron transfer from the heme-oxo moiety to form water and Cpd I. This study enables us to generalize the mechanisms of O-O activation, elucidated so far by QM/MM calculations, for other heme enzymes, e.g., cytochrome P450cam, horseradish peroxidase (HRP), nitric oxide synthase (NOS), and heme oxygenase (HO). Much like for CPO, in the cases of P450 and HRP, the PCET lowers the barrier below the purely homolytic cleavage alternative (in our case, the homolytic mechanism is calculated directly from FeIII-HOOH). By contrast, the absence of PCET in HO, along with the robust water cluster, prefers a homolytic cleavage mechanism.
authors.affiliation: Institute of Chemistry and The Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Hajime
authors.initials: H
authors.lastname: Hirao
authors.forename: Etienne
authors.initials: E
authors.lastname: Derat
authors.forename: Ilme
authors.initials: I
authors.lastname: Schlichting
authors.forename: Sason
authors.initials: S
authors.lastname: Shaik
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D002711:Chloride Peroxidase / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D006418:Heme / Q000737:chemistry* / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D017665:Hydroxyl Radical / Q000737:chemistry; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D017434:Protein Structure, Tertiary
chemical_list: D017665:Hydroxyl Radical; D006418:Heme; D006861:Hydrogen Peroxide; D007501:Iron; D002711:Chloride Peroxidase