title: Structural insights into human microsomal epoxide hydrolase by combined homology modeling, molecular dynamics simulations, and molecular docking calculations.
abstract: A new homology model of human microsomal epoxide hydrolase was derived based on multiple templates. The model obtained was fully evaluated, including MD simulations and ensemble-based docking, showing that the quality of the structure is better than that of only previously known model. Particularly, a catalytic triad was clearly identified, in agreement with the experimental information available. Analysis of intermediates in the enzymatic mechanism led to the identification of key residues for substrate binding, stereoselectivity, and intermediate stabilization during the reaction. In particular, we have confirmed the role of the oxyanion hole and the conserved motif (HGXP) in epoxide hydrolases, in excellent agreement with known experimental and computational data on similar systems. The model obtained is the first one that fully agrees with all the experimental observations on the system. Proteins 2017; 85:720-730. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Computational Chemistry and Biology Group, Facultad de Química, UdelaR, Isidoro de María 1614, Montevideo, 11800, Uruguay.|Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, 405 30, Sweden.
authors.forename: Patricia
authors.identifier: 0000-0002-6711-4972
authors.initials: P
authors.lastname: Saenz-Méndez
authors.affiliation: Computational Chemistry and Biology Group, Facultad de Química, UdelaR, Isidoro de María 1614, Montevideo, 11800, Uruguay.
authors.forename: Aline
authors.initials: A
authors.lastname: Katz
authors.affiliation: Pharmaceutical Science Department, Facultad de Química, UdelaR, General Flores 2124, Montevideo, 11800, Uruguay.
authors.forename: María Lucía
authors.initials: ML
authors.lastname: Pérez-Kempner
authors.affiliation: Computational Chemistry and Biology Group, Facultad de Química, UdelaR, Isidoro de María 1614, Montevideo, 11800, Uruguay.
authors.forename: Oscar N
authors.initials: ON
authors.lastname: Ventura
authors.affiliation: Pharmaceutical Science Department, Facultad de Química, UdelaR, General Flores 2124, Montevideo, 11800, Uruguay.
authors.forename: Marta
authors.initials: M
authors.lastname: Vázquez
mesh_terms: D000595:Amino Acid Sequence; D001234:Aspergillus niger / Q000737:chemistry / Q000201:enzymology; D020134:Catalytic Domain; D017124:Conserved Sequence; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000737:chemistry* / Q000201:enzymology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013302:Streptomyces / Q000737:chemistry / Q000201:enzymology; D040681:Structural Homology, Protein; D013379:Substrate Specificity; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D014635:Valproic Acid; C013690:styrene oxide; D004851:Epoxide Hydrolases; C004651:dipropylacetamide
keywords: clustering; ensemble-based docking; epilepsy; homology models; microsomal epoxide hydrolase