Effect of Cytochrome P450 3A4 Genetic Polymorphisms on Heme Recognition by Using Molecular Dynamics Simulations

CYP3A4 is a drug-metabolizing enzyme involved in the metabolism of numerous drugs, and genetic polymorphisms of CYP3A4 can influence individual differences in drug toxicity and efficacy. For some variants, it has been reported that not only were the enzymatic activities reduced, but also the 450 nm absorption spectra in the presence of CO were lost. In this study, molecular dynamics simulations of CYP3A4.1, CYP3A4.8, CYP3A4.12, and CYP3A4.17 for which 450 nm absorption spectra were not observed were performed to predict the three-dimensional (3D) structures and evaluate the effects of amino acid mutations on such structures. By comparing the 3D structures of these variants with the wild-type CYP3A4.1, the impact of the mutations on heme recognition within CYP3A4 was clarified. Analysis of structural flexibility and hydrogen bond networks revealed significant changes in active site interactions and conformation, suggesting these alterations likely affected heme recognition. Furthermore, not only the direct interactions between the mutation site and heme but also the effects of the mutations on the surrounding structure were estimated.