Article ; Online: Insights into the binding mechanism between α-TOH and CYP4F2: A homology modeling, molecular docking, and molecular dynamics simulation study.
Journal of cellular biochemistry
2023 Volume 124, Issue 4, Page(s) 573–585
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 ...
| 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. |
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| MeSH term(s) | Humans ; alpha-Tocopherol/metabolism ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Cytochrome P450 Family 4/genetics ; Cytochrome P450 Family 4/metabolism ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/metabolism |
| Chemical Substances | alpha-Tocopherol (H4N855PNZ1) ; Cytochrome P450 Family 4 (EC 1.14.14.1) ; Cytochrome P-450 Enzyme System (9035-51-2) ; CYP4F2 protein, human (EC 1.14.14.78) |
| Language | English |
| Publishing date | 2023-03-15 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 392402-6 |
| ISSN | 1097-4644 ; 0730-2312 |
| ISSN (online) | 1097-4644 |
| ISSN | 0730-2312 |
| DOI | 10.1002/jcb.30391 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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