How Mutations Affecting the Ligand-receptor Interactions:a Combined MD and QM/MM Calculation on CYP2E1 and Its Two Mutants

Cytochrome P450(CYP) 2E1 is a dual function monoxygenase with a crucial role in the metabolism of 6% of drugs on the market at present. The enzyme is of tremendous interest for its association with alcohol consumption, diabetes, obesity and fasting. Despite the abundant experimental mutagenesis data, the molecular origin and the structural motifs for the enzymatic activity deficiencies have not been rationalized at the atomic level. In this regard, we have investigated the effects of mutation on the structural and energetic characteristics upon single point mutations in CYP2E1, N219D and S366C. The molecular dynamics(MD) simulation combined with quantum mechanics/molecular mechanics(QM/MM) and noncovalent interaction(NCI) analysis was carried out on CYP2E1 and its two mutants. The results highlight the critical role of Phe207, which is responsible for both structural flexibility and energetic variation, shortening the gap between the theory and the experimentally observed results of enzymatic activity decrease. The underlying molecular mechanism of the enzymatic activity deficiencies for mutants may be attributed to the changes of spatial position of Phe207 in the two mutants. This work provides particular explanations to how mutations affect ligand-receptor interactions based on combined MD and QM/MM calculations. Furthermore, the mutational effects on the activity of CYP2E1 obtained in the present study are beneficial to both the experimental and the computational works of CYPs and may allow researchers to achieve desirable changes in enzymatic activity.