Prediction of three-dimensional structures and structural flexibilities of wild-type and mutant cytochrome P450 1A2 using molecular dynamics simulations

• The static structures of CYP1A2 genetic variants were computationally predicted.
• Only one amino acid mutation may change the overall structure of CYP1A2.
• The structural flexibilities of some mutant CYP1A2 were different from wild type.
• The dynamic property of CYP1A2 may be involved to the enzymatic function.

In this study, we investigated the effect of genetic polymorphism on the three-dimensional (3D) conformation of cytochrome P450 1A2 (CYP1A2) using molecular dynamics (MD) simulations. CYP1A2, a major drug-metabolizing enzyme among cytochrome P450 enzymes (CYPs), is known to have many variant alleles. The genetic polymorphism of CYP1A2 may cause individual differences in the pharmacokinetics of medicines. By performing 100 ns or longer MD simulations, we investigated the influence of amino acid mutation on the 3D structures and the dynamic properties of proteins. The results show that the static structures were changed by the mutations of amino acid residues, not only near the mutated residues but also in distant portions of the proteins. Moreover, the mutation of only one amino acid was shown to change the structural flexibility of proteins, which may influence the substrate recognition and enzymatic activity. Our results clearly suggest that it is necessary to investigate the dynamic property as well as the static 3D structure for understanding the change of the enzymatic activity of mutant CYP1A2.

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