Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: A functional and structural impact

Abstract Background Cytochrome P450 4F2 (CYP4F2) enzyme is one of the CYP4 family responsible for the metabolism of fatty acids, therapeutic drugs, and signaling molecules, such as arachidonic acid, tocopherols, and vitamin K. Several reports have demonstrated that missense variant CYP4F2*3 (V433M) cause decreased activity of CYP4F2 and inter-individual variations in warfarin dose in different ethnic groups. However, the molecular pathogenicity mechanism of missense V433M on the CYP4F2 protein at the atomic level has not yet been completely elucidated. Methods and results In the current study, we evaluate the effect of V433M substitution on the CYP4F2 enzyme through 11 different bioinformatics tools. Further molecular dynamics (MD) simulation was applied to assess the impact of V433M mutation on CYP4F2 protein structure, stability, and dynamics. Also, the molecular docking method was performed to illustrate the effect of V433M on its interaction with vitamin K. Based on our results, the CYP4F2*3 variant is a damaging polymorphism with destabilizing nature. Simulation results presented that missense V433M affects the dynamics and stability of CYP4F2 by reducing its compactness and stability, which means its tendency to change the overall structural conformation and flexibility of CYP4F2. The docking result showed that the CYP4F2*3 variant decreased binding affinity between vitamin K1 and CYP4F2 enzyme, which caused less activity of CYP4F2*3 compared to native CYP4F2. Conclusions This investigation determined the molecular pathogenicity mechanism of the CYP4F2*3 variant on the human CYP4F2 protein and supplied new information for comprehending the structure-function relationship in CYP4F2 and other CYP4 enzymes. These findings will help to develop effective drugs and individual treatment options.