title: Prediction of three-dimensional structures and structural flexibilities of wild-type and mutant cytochrome P450 1A2 using molecular dynamics simulations.
abstract: 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 100ns 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.
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Yurie
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Fukuyoshi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiratsuka
authors.affiliation: School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamaotsu
authors.affiliation: School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.affiliation: Fuculty of Pharmaceutical Science, Tohoku Pharmaceutical University, Aoba-ku, Sendai, Miyagi, Japan.
authors.forename: Ohgi
authors.initials: O
authors.lastname: Takahashi
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; Institute for Protein Research, Osaka University, Suita, Osaka, Japan. Electronic address: oda@p.kanazawa-u.ac.jp.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Oda
mesh_terms: D020134:Catalytic Domain; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry*; D006418:Heme / Q000737:chemistry; D006860:Hydrogen Bonding; D008024:Ligands; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D017433:Protein Structure, Secondary; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D050505:Mutant Proteins; D010455:Peptides; D014867:Water; D006418:Heme; D019388:Cytochrome P-450 CYP1A2