Will P450cam hydroxylate or desaturate alkanes? QM and QM/MM studies

Wenzhen Lai, Hui Chen, Shimrit Cohen, Sason Shaik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

The hydroxylation versus desaturation for the enzyme P450cam is addressed by comparing the reactivity of the active species Por •+Fe(IV)=O (Cpd I) toward cyclohexane (CH), camphor (CAM), and cyclohexene (CHE). The quantum mechanics (QM)-only calculations, which reveal protein-free trends, show mixed and nonselective hydroxylation/desaturation activities, branching from the PorFe(IV)OH/R• intermediates. By contrast, the quantum mechanics/molecular mechanics (QM/MM) results with CAM and CHE show exclusive alcohol formation. Two distinct modes by which the protein controls the hydroxylation/desaturation selectivity were identified: (a) with the native substrate CAM, the tight binding site of the P450cam protein prevents the second hydrogen abstraction and leads to exclusive C5-H hydroxylation, and (b) with the freely tumbling CHE, the protein stabilizes the polarizable electromers, Por•+Fe(III)OH/R•, which possess intrinsic hydroxylase preference. The latter mechanism is common for substrates that are not tightly bound. It is a unique mechanism to P450 Cpd I, which possesses the Por•+Fe(III)OH electromers that dominate the in-protein reactivity. This is contrasted with nonheme enzymes, which lack such electromers.

Original languageEnglish
Pages (from-to)2229-2235
Number of pages7
JournalJournal of Physical Chemistry Letters
Volume2
Issue number17
DOIs
StatePublished - 1 Sep 2011

Keywords

  • Biophysical Chemistry

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