Prediction of activation energies for aromatic oxidation by cytochrome P450

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Patrik Rydberg, Ulf Ryde, Lars Olsen

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.
Original languageEnglish
JournalJournal of Physical Chemistry A
Volume112
Issue number50
Pages (from-to)13058-13065
ISSN1089-5639
DOIs
Publication statusPublished - 2008

ID: 8568055