Valence Bond Insights into the H-Abstraction Barrier in Cytochrome P450.

The valence bond (VB) framework is widely recognized as a powerful tool for elucidating the electronic origins of activation energy barriers in chemical reactions. We employed ab initio VB calculations to investigate the hydrogen abstraction (H-abstraction) barrier in cytochrome P450 enzymes (P450s), using a simplified model in which an oriented external electric field (OEEF) was applied to efficiently capture the electronic effects of the equatorial porphyrin and proximal thiolate ligands on the iron(IV)-oxo unit in compound I (Cpd I). Methane (CH) was used as the model substrate. The VB-calculated barrier height, evaluated with this simplified model, qualitatively reproduced the barrier predicted by density functional theory (DFT) calculations using a more complete active-site model. Additionally, by examining the weights and diagonal elements of the Hamiltonian matrix for different VB structures along the reaction coordinate, we identified key VB structures-including covalent and ionic configurations representing the C-H and O-H bonds-that contribute significantly to the electronic origin of the barrier height. The mixing of these distinct VB structures leads to resonance stabilization, which is maximized at the transition state.