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The Reaction Mechanism of Cytochrome P450 NO Reductase: A Detailed Quantum Mechanics/Molecular Mechanics Study
Author(s) -
Riplinger Christoph,
Neese Frank
Publication year - 2011
Publication title -
chemphyschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.016
H-Index - 140
eISSN - 1439-7641
pISSN - 1439-4235
DOI - 10.1002/cphc.201100523
Subject(s) - diradical , chemistry , kinetic isotope effect , computational chemistry , reaction intermediate , reaction mechanism , active site , molecular mechanics , singlet state , hydride , stereochemistry , electron transfer , reactive intermediate , reactivity (psychology) , photochemistry , hydrogen , molecular dynamics , enzyme , excited state , deuterium , catalysis , organic chemistry , medicine , physics , alternative medicine , quantum mechanics , pathology , nuclear physics
A detailed QM/MM study on the reaction mechanism of Cytochrome P450 NO reductase is reported. Two reaction pathways connecting the two well‐characterized intermediates as well as two putative intermediates that represent the unknown third intermediate are explored, with emphasis on the unusual direct reduction of the enzymatic active site by the cofactor NADH. Activation barriers and kinetic isotope effect are calculated and reveal that reduction of the NO‐bound species occurs in form of a hydride ion transfer. Furthermore, the impact of different hydrogen bonds in the active site to binding and reactivity of NADH is explored. The calculated kinetic and thermodynamic properties for both modelled pathways are used for the kinetic simulation of the entire reaction course. It is thus shown that the unknown key intermediate is the singlet diradical Fe III ‐NHOH ⋅ . It is also found that the mechanism of the NN bond formation is spin‐recoupling, which is only possible due to the diradical character of the key intermediate.