Investigation of ligand selectivity in CYP3A7 by molecular dynamics simulations
Cytochrome P450(CYP)3A7 plays a crucial role in die biotransformation of the metabolized endogenous and exogenous steroids.To compare the metabolic capabilities of CYP3A7 ligands complexes,three endogenous ligands were selected,namely dehydroepiandroslerone(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.
cytochrome P450 3A7 homology modeling molecular docking molecular dynamics simulation MM-GB/ SA calculation
Jing-Rong Fan Qing-Chuan Zheng Ying-Lu Cui Wei-Kang Li Hong-Xing Zhang
International Joint Research Laboratory of Nano-Micro Architecture Chemistry,State Key Laboratory of International Joint Research Laboratory of Nano-Micro Architecture Chemistry,State Key Laboratory of
国内会议
大连
英文
520-528
2016-09-24（万方平台首次上网日期，不代表论文的发表时间）