| Abstract
| - The interaction between nitric oxide (NO) and the active site of ferric cytochrome P450 was studied by meansof density functional theory (DFT), at the generalized gradient approximation level, and of the SAM1 semiempiricalmethod. The electrostatic effects of the protein environment were included in our DFT scheme by using a hybridquantum classical approach. The active-site model consisted of an iron(III) porphyrin, the adjacent cysteine residue,and one coordinated water molecule. For this system, spin populations and relative energies for selected spinstates were computed. Interestingly, the unpaired electron density, the HOMO, and the LUMO were found to behighly localized on the iron and in an appreciable extent on the sulfur coordinated to the metal. This providescentral information about the reactivity of nitric oxide with the active site. Since the substitution of a moleculeof H2O by NO has been proposed as being responsible for the inhibition of the cytochrome in the presence ofnitric oxide, we have analyzed the thermodynamic feasibility of the ligand exchange process. The structure of thenitrosylated active site was partially optimized using SAM1. A low-spin ground state was obtained for the nitrosylcomplex, with a linear Fe−N−O angle. The trends found in Fe−N−O angles and Fe−N lengths of the higherenergy spin states provided a notable insight into the electronic configuration of the complex within the frameworkof the Enemark and Feltham formalism. In relation to the protein environment, it was assessed that the electrostaticfield has significant effects on several computed properties. However, in both vacuum and protein environments,the ligand exchange reaction turned out to be exergonic and the relative orders of spin states of the relevantspecies were the same.
- Recent studies have shown that nitric oxide (NO) inhibits the cytochrome P450 enzyme. In this work density functional theory and the SAM1 semiempirical methods were used to study the interaction between NO and the active site of the enzyme. The thermodynamic feasibility of the displacement of H2O by NO in the active site as a mechanism of inhibition was assessed. Unpaired spin populations and Fukui functions were also analyzed to obtain local reactivity information.
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