Structural insights into human microsomal epoxide hydrolase by combined homology modeling,molecular dynamics simulations,and molecular docking calculations |
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| Authors: | Patricia Saenz‐Méndez Aline Katz María Lucía Pérez‐Kempner Oscar N Ventura Marta Vázquez |
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| Institution: | 1. Computational Chemistry and Biology Group, Facultad de Química, Montevideo, Uruguay;2. Department of Chemistry and Molecular Biology, University of Gothenburg, G?teborg, Sweden;3. Pharmaceutical Science Department, Facultad de Química, Montevideo, Uruguay |
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| 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. |
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| Keywords: | microsomal epoxide hydrolase homology models clustering ensemble‐based docking epilepsy |
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