Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 126, Issue 27, Pages 8501-8508Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja036123b
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- NIGMS NIH HHS [GM 40526] Funding Source: Medline
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The catalytic pathway of cytochrome P450cam is studied by means of a hybrid quantum mechanics/molecular mechanics method. Our results reveal an active role of the enzyme in the different catalytic steps. The protein initially controls the energy gap between the high- and low-spin states in the substrate binding process, allowing thermodynamic reduction by putidaredoxin reductase and molecular oxygen addition. A second electron reduction activates the delivery of protons to the active site through a selective interaction of Thr252 and the distal oxygen causing the O-O cleavage. Finally, the protein environment catalyzes the substrate hydrogen atom abstraction step with a remarkably low free energy barrier (similar to8 kcal/mol). Our results are consistent with the effect of mutations on the enzymatic efficacy and provide a satisfactory explanation for the experimental failure to trap the proposed catalytically competent species, a ferryl Fe(IV) heme.
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