title: Investigation of indazole unbinding pathways in CYP2E1 by molecular dynamics simulations.
abstract: Human microsomal cytochrome P450 2E1 (CYP2E1) can oxidize not only low molecular weight xenobiotic compounds such as ethanol, but also many endogenous fatty acids. The crystal structure of CYP2E1 in complex with indazole reveals that the active site is deeply buried into the protein center. Thus, the unbinding pathways and associated unbinding mechanisms remain elusive. In this study, random acceleration molecular dynamics simulations combined with steered molecular dynamics and potential of mean force calculations were performed to identify the possible unbinding pathways in CYP2E1. The results show that channel 2c and 2a are most likely the unbinding channels of CYP2E1. The former channel is located between helices G and I and the B-C loop, and the latter resides between the region formed by the F-G loop, the B-C loop and the β1 sheet. Phe298 and Phe478 act as the gate keeper during indazole unbinding along channel 2c and 2a, respectively. Previous site-directed mutagenesis experiments also supported these findings.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Shen
authors.forename: Feixiong
authors.initials: F
authors.lastname: Cheng
authors.forename: You
authors.initials: Y
authors.lastname: Xu
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.forename: Wen
authors.initials: W
authors.lastname: Xiao
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Guixia
authors.initials: G
authors.lastname: Liu
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D006801:Humans; D007191:Indazoles / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D007191:Indazoles; D003577:Cytochrome P-450 Enzyme System; C110332:CYP2F1 protein, human; D000072467:Cytochrome P450 Family 2