Insights into the binding mechanism between α‐TOH and CYP4F2: A homology modeling, molecular docking, and molecular dynamics simulation study

Abstract α‐Tocopherol (α‐TOH) is a potent antioxidant. The concentrations of α‐TOH in plasma are closely related to human health. α‐TOH can be regulated by the metabolism of cytochrome P450 4F2 (CYP4F2). However, the atomic‐level basis for this regulation process remains elusive. Here, we successfully constructed the structure of CYP4F2 by homology modeling and obtained the α‐TOH–CYP4F2 complex models using molecular docking. Three parallel 500 ns molecular dynamics simulations were performed on each complex model to investigate the details of the interaction between α‐TOH and CYP4F2. MM–GBSA method combined with principal component analysis shows that 8 key residues establish a hydrophobic cavity stabilizing α‐TOH in the pocket of CYP4F2 and S423 forms an important hydrogen bond with α‐TOH anchoring α‐TOH in the favorable position for ω‐hydroxylation. Based on our simulation results and the experimental facts, we designed mutation simulation experiments to clarify the important role of two key residues (S423 and V433) in the binding of α‐TOH with CYP4F2. The results show that the mutations directly or indirectly change the binding mode of α‐TOH and decrease its binding affinity with CYP4F2, which is unfavorable for ω‐hydroxylation. Our results could enrich the information on structure‐function relationships of CYP4F2 and provide valuable insights into the regulatory mechanism of CYP4F2 on the metabolism of α‐TOH.