互为同分异构体的植物雌激素与ER_(α)及ER_(β)结合亲和力的分子动力学研究

Study of the binding affinity of isomers phytoestrogens to ER_(α) and ER_(β) by molecular dynamics simulations

本研究采用分子动力学模拟方法探究了互为同分异构体的2种植物雌激素芹菜素和染料木素与雌激素受体ER_(α)及ER_(β)之间的结合亲和力,选择内源性激素17β-雌二醇进行对比研究.研究结果表明,配体中官能团的位置、配体和受体之间形成的氢键数目、范德华能、静电能及溶剂化能等相互作用影响复合物的稳定性,进而影响结合能力.

In this study,molecular simulation methods including molecular docking and molecular dynamics(MD)were performed to study the binding affinity of two isomers(apigenin and genistein)to estrogen receptors ER_(α)and ER_(β),respectively.Meanwhile,the 17β-estradiol was selected as a reference to compare the differences of binding ability from the above isomers phytoestrogens.In order to confirm the structural stability of the complexes,the ligands and each amino acid in the complexes during the simulation process,the root mean square deviation(RMSD)and the root means square fluctuation(RMSF)values were calculated.The binding patterns analysis showed that there are 3,3 and 3 hydrogen bonds formed by 17β-Estradiol,apigenin and genistein with the ER_(α),while 3,2 and 3 with the ER_(β).The results of the hydrogen bond occupancy analysis showed that the hydrogen bond occupancy(>10%)of 17β-estradiol was higher than that of phytoestrogens genistein and apigenin in both of interaction with ER_(α)and ER_(β).Moreover,all the three compounds have the higher hydrogen bond occupancy with ER_(β)than with ER_(α),indicating the higher selectivity of ER_(β).The hydrophobic interaction analysis of the complexes in the last 20 ns of the MD simulation showed that the amino acid residues at the pocket of the ligand-protein binding are mostly hydrophobic in nature,creating hydrophobic interactions with receptors,and further maintaining the stability of the complexes.The hydrophobic amino acids at the left and bottom of the binding cavity are greater than other locations.The binding free energy analysis showed that van der Waals energy,electrostatic energy and non-polar solvation energy are the major energies and give the positive effects to the complexes formed.Furthermore,it confirms that the three compounds have greater affinity for ER_(β)than ER_(α),which is consistent with the above analysis.The binding free energy decomposition analysis showed that the number of key amino acids contributing to the free energy of genistein and apigenin were 8,10 and 7,8 for ER_(α)and ER_(β),respectively.All in all,this study indicated that the formation of hydrogen bond and hydrophobic interaction have an important effect on the stability of the complexes.Further,the calculation and decomposition of binding free energy explored that Van der Waals energy,electrostatic energy and solvation energy affect the stability of the complex mainly,thereby affecting the binding ability.