Quantum mechanical/molecular mechanical study on the mechanisms of Compound I formation in the catalytic cycle of chloroperoxidase : An overview on heme enzymes

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

51 Scopus Citations
View graph of relations

Author(s)

  • Hui Chen
  • Hajime Hirao
  • Etienne Derat
  • Ilme Schlichting
  • Sason Shaik

Detail(s)

Original languageEnglish
Pages (from-to)9490-9500
Journal / PublicationJournal of Physical Chemistry B
Volume112
Issue number31
Publication statusPublished - 7 Aug 2008
Externally publishedYes

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 Fe III-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. © 2008 American Chemical Society.

Citation Format(s)

Quantum mechanical/molecular mechanical study on the mechanisms of Compound I formation in the catalytic cycle of chloroperoxidase : An overview on heme enzymes. / Chen, Hui; Hirao, Hajime; Derat, Etienne; Schlichting, Ilme; Shaik, Sason.

In: Journal of Physical Chemistry B, Vol. 112, No. 31, 07.08.2008, p. 9490-9500.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review