Abstract: To study the reaction of cytochrome enzyme P450 (CYP) 4F12 catalyzed by arachidonic acid (AA), we used density functional theory (DFT), homology modeling, molecular docking, and molecular dynamics (MD) simulations to perform a computational study on the interaction of CYP4F12 and arachidonic acid (AA). The DFT calculation based on the model of arachidonic acid and heme group showed that the energy barrier of hydroxylation at the ω-2 site was about 5-26 kJ/mol lower than that of other potential metabolic sites. The results of ERRAT and PROCHECK confirmed that the modeled protein has a good quality.The results of molecular docking and molecular dynamics simulations showed that the ω-2 site was more accessible to active oxygen atoms in the catalytic process, and the amino acid residues ASN122 and SER399 near the active site played a major role in stabilizing the substrate. Binding free energy analysis also showed that the amino acid residues ASN122 and SER399 had a significant contribution to catalysis. Our research revealed the binding mode of arachidonic acid catalyzed by CYP4F12, which provided research ideas and theoretical guidance for the study of CYP 4 enzymes.

Key words: cytochrome P450 4F12 (CYP4F12), density functional theory, molecular dynamics simulation