Joint Use of Bonding Evolution Theory and QM/MM Hybrid Method for Understanding the Hydrogen Abstraction Mechanism via Cytochrome P450 Aromatase

Bonding evolution theory (BET), as a combination of the electron localization function (ELF) and Thom’s catastrophe theory (CT), has been coupled with quantum mechanics/molecular mechanics (QM/MM) method in order to study biochemical reaction paths. The evolution of the bond breaking/forming processes and electron pair rearrangements in an inhomogeneous dynamic environment provided by the enzyme has been elucidated. The proposed methodology is applied in an enzymatic system in order to clarify the reaction mechanism for the hydrogen abstraction of the androstenedione (ASD) substrate catalyzed by the cytochrome P450 aromatase enzyme. The use of a QM/MM Hamiltonian allows inclusion of the polarization of the charges derived from the amino acid residues in the wave function, providing a more accurate and realistic description of the chemical process. The hydrogen abstraction step is found to have five different ELF structural stability domains, whereas the C–H breaking and O–H forming bond process rearrangements are taking place in an asynchronous way.