title: Prediction of activation energies for aromatic oxidation by cytochrome P450.
abstract: We have estimated the activation energy for aromatic oxidation by compound I in cytochrome P450 for a diverse set of 17 substrates using state-of-the-art density functional theory (B3LYP) with large basis sets. The activation energies vary from 60 to 87 kJ/mol. We then test if these results can be reproduced by computationally less demanding methods. The best methods (a B3LYP calculation of the activation energy of a methoxy-radical model or a partial least-squares model of the semiempirical AM1 bond dissociation energies and spin densities of the tetrahedral intermediate for both a hydroxyl-cation and a hydroxyl-radical model) give correlations with r(2) of 0.8 and mean absolute deviations of 3 kJ/mol. Finally, we apply these simpler methods on several sets of reactions for which experimental data are available and show that we can predict the reactive sites by combining calculations of the activation energies with the solvent-accessible surface area of each site.
authors.affiliation: Department of Medicinal Chemistry, Copenhagen University, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rydberg
authors.forename: Ulf
authors.initials: U
authors.lastname: Ryde
authors.forename: Lars
authors.initials: L
authors.lastname: Olsen
mesh_terms: D000465:Algorithms; D001554:Benzene / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002151:Calorimetry; D020134:Catalytic Domain; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D016018:Least-Squares Analysis; D008962:Models, Theoretical; D010084:Oxidation-Reduction; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D005609:Free Radicals; D003577:Cytochrome P-450 Enzyme System; D001554:Benzene