The Poulos-Kraut mechanism of Compound I formation in horseradish peroxidase: A QM/MM Study

Etienne Derat, Sason Shaik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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(H 2O2) 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.

Original languageEnglish
Pages (from-to)10526-10533
Number of pages8
JournalJournal of Physical Chemistry B
Volume110
Issue number21
DOIs
StatePublished - 1 Jun 2006

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