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Compound I in heme thiolate enzymes: a comparative QM/MM study
Kyung-Bin Cho1, Hajime Hirao, Hui Chen
1Department of Organic Chemistry and The Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
The Journal of Physical Chemistry. A
|October 15, 2008
Summary
This study compares heme enzyme Compound I (Cpd I) structures across heme-thiolate enzymes. While generally similar, the nitric oxide synthase (NOS) enzyme shows distinct Cpd I characteristics due to its unique electrical field.
Area of Science:
- Biochemistry
- Computational Chemistry
- Enzymology
Background:
- Heme enzymes, particularly heme-thiolate enzymes, play crucial roles in biological oxidation reactions.
- Compound I (Cpd I) is the key active species in many heme enzymes, but its structure and reactivity can vary.
- Understanding Cpd I variations is essential for elucidating enzyme mechanisms and designing inhibitors.
Purpose of the Study:
- To directly compare the electronic structures of Compound I (Cpd I) across various heme-thiolate enzymes.
- To investigate the influence of the protein environment on Cpd I structure and properties.
- To provide a computational basis for experimental studies of Cpd I in different enzymes.
Main Methods:
- Hybrid quantum mechanical/molecular mechanical (QM/MM) calculations were employed to model Cpd I structures.
- Sixty-four different Cpd I structures were computed for four enzymes: P450(cam), P450(cam)-L358P mutant, cytochrome P450-peroxygenase (CPO), and nitric oxide synthase (NOS).
- Calculations considered varying QM region sizes and spin multiplicities, and Mossbauer parameters were predicted.
Main Results:
- Compound I species across the studied heme-thiolate enzymes exhibit significant similarities in key features.
- The enzyme's electrical field profoundly influences Cpd I, altering it compared to gas-phase structures.
- Nitric oxide synthase (NOS) displays distinct Cpd I characteristics, attributed to a planar electrical field at the heme, unlike the perpendicular field in other enzymes.
- The P450(cam) mutant L358P showed minimal changes in Cpd I upon hydrogen bond disruption.
Conclusions:
- Compound I structures are broadly conserved across heme-thiolate enzymes, suggesting CPO Cpd I can model P450 Cpd I experimentally.
- The protein's electrical field is a critical determinant of Cpd I structure and properties, with NOS being a notable exception.
- Computational predictions of Mossbauer parameters will facilitate experimental validation and further research into Cpd I variations.
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