Inclusion of Dispersion Effects Significantly Improves Accuracy of Calculated Reaction Barriers for Cytochrome P450 Catalyzed Reactions

Prediction of cytochrome P450 reactivity is of great importance to the development of new medicinal compounds. Density functional theory (DFT) has proven itself as a useful tool in the characterization of the elusive reactive species, compound I, and of the mechanisms of substrate oxidation. B3LYP is the most widely used density functional in the study of P450s; however, a major drawback of B3LYP is its inaccurate treatment of dispersion, leading to discrepancies between experiment and theory in some systems. Recent work has shown that an added empirical dispersion correction to B3LYP (B3LYP-D) yields more promising results for similar systems. In the present work, two previously studied systems, camphor hydroxylation and alkene oxidation, have been recalculated using B3LYP-D. Our work shows that inclusion of dispersion has a significant effect on the energies and geometries of transition states and encounter complexes; furthermore, an improved agreement with experimental data is observed.