title: Investigation of ligand selectivity in CYP3A7 by molecular dynamics simulations.
abstract: Cytochrome P450 (CYP) 3A7 plays a crucial role in the biotransformation of the metabolized endogenous and exogenous steroids. To compare the metabolic capabilities of CYP3A7-ligands complexes, three endogenous ligands were selected, namely dehydroepiandrosterone (DHEA), estrone, and estradiol. In this study, a three-dimensional model of CYP3A7 was constructed by homology modeling using the crystal structure of CYP3A4 as the template and refined by molecular dynamics simulation (MD). The docking method was adopted, combined with MD simulation and the molecular mechanics generalized born surface area method, to probe the ligand selectivity of CYP3A7. These results demonstrate that DHEA has the highest binding affinity, and the results of the binding free energy were in accordance with the experimental conclusion that estrone is better than estradiol. Moreover, several key residues responsible for substrate specificity were identified on the enzyme. Arg372 may be the most important residue due to the low interaction energies and the existence of hydrogen bond with DHEA throughout simulation. In addition, a cluster of Phe residues provides a hydrophobic environment to stabilize ligands. This study provides insights into the structural features of CYP3A7, which could contribute to further understanding of related protein structures and dynamics.
authors.affiliation: a International Joint Research Laboratory of Nano-Micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry , Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , People's Republic of China.
authors.forename: Jing-Rong
authors.initials: JR
authors.lastname: Fan
authors.affiliation: a International Joint Research Laboratory of Nano-Micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry , Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , People's Republic of China.|b Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , Jilin University , Changchun , Jilin 130023 , People's Republic of China.
authors.forename: Qing-Chuan
authors.initials: QC
authors.lastname: Zheng
authors.affiliation: a International Joint Research Laboratory of Nano-Micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry , Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , People's Republic of China.
authors.forename: Ying-Lu
authors.initials: YL
authors.lastname: Cui
authors.affiliation: a International Joint Research Laboratory of Nano-Micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry , Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , People's Republic of China.
authors.forename: Wei-Kang
authors.initials: WK
authors.lastname: Li
authors.affiliation: a International Joint Research Laboratory of Nano-Micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry , Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , People's Republic of China.
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D051544:Cytochrome P-450 CYP3A; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D001189:Aryl Hydrocarbon Hydroxylases; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A
keywords: MM-GB/SA calculation; cytochrome P450 3A7; homology modeling; molecular docking; molecular dynamics simulation