Investigation of ligand selectivity in CYP3A7 by molecular dynamics simulationsby Jing-Rong Fan, Qing-Chuan Zheng, Ying-Lu Cui, Wei-Kang Li, Hong-Xing Zhang

Journal of Biomolecular Structure and Dynamics

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Year
2015
DOI
10.1080/07391102.2015.1054884
Subject
Molecular Biology / Structural Biology

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Investigation of Ligand Selectivity in CYP3A7 by

Molecular Dynamics Simulations

Jing-Rong Fana, Qing-Chuan Zhengab, Ying-Lu Cuia, Wei-Kang Lia & Hong-Xing Zhanga 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

Accepted author version posted online: 12 Jun 2015.

To cite this article: Jing-Rong Fan, Qing-Chuan Zheng, Ying-Lu Cui, Wei-Kang Li & Hong-Xing Zhang (2015): Investigation of Ligand Selectivity in CYP3A7 by Molecular Dynamics Simulations, Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2015.1054884

To link to this article: http://dx.doi.org/10.1080/07391102.2015.1054884

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Publisher: Taylor & Francis

Journal: Journal of Biomolecular Structure and Dynamics

DOI: http://dx.doi.org/10.1080/07391102.2015.1054884

Investigation of Ligand Selectivity in CYP3A7 by Molecular

Dynamics Simulations

Jing-Rong Fana, Qing-Chuan Zhenga,b*, Ying-Lu Cuia, Wei-Kang Lia, Hong-Xing

Zhanga aInternational 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 bKey Laboratory for Molecular Enzymology and Engineering of the Ministry of

Education, Jilin University, Changchun, Jilin, 130023, People’s Republic of China

Corresponding author:

Qing-Chuan Zheng

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

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Li bra ry] at 10 :20 15

Ju ne 20 15 2

People’s Republic of China

Fax: (+86) 431-8849-8966

E-mail address: zhengqc@jlu.edu.cn

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 (MM-GB/SA) 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 as 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. The present study provides insights into the structural features of CYP3A7, which could contribute to further understanding of related protein structures and dynamics.

Keywords: cytochrome P450 3A7; homology modeling; molecular docking;

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Ju ne 20 15 3 molecular dynamics simulation; MM-GB/SA calculation 1. Introduction

Cytochrome P450s (CYPs) constitute a superfamily of heme-containing monooxygenases that are ubiquitious in both eukaryotes and prokaryotes. The CYP enzymes metabolize a wide variety of endogenous compounds (steroids, fatty acids, and prostaglandins) and exogenous chemicals including drugs, carcinogens and environmental pollutants (Cui et al., 2013; Cui et al., 2013; Denisov, Makris, Sligar, & Schlichting, 2005; Li et al., 2008; Park, Lee, & Suh, 2005). The active site of CYPs contains a heme group which is deeply buried in the protein core and the iron atom is covalently bound to a conserved cysteine (Shen et al., 2012).