薛峤,
张爱茜,
中国科学院生态环境研究中心 环境化学与生态毒理学国家重点实验室, 北京 100085
作者简介: 朱婧涵(1992-),女,研究生,研究方向为理论环境化学,E-mail:nanaqq7@hotmail.com.
通讯作者: 张爱茜,aqzhang@rcees.ac.cn
基金项目: 国家自然科学基金(21507152,21277164)中国科学院战略性先导科技专项课题(XDB14030500)
国家高技术研究发展计划(863计划)(2013AA065201)
中图分类号: X171.5
Structural Basis and Molecular Mechanism for Selective Binding of 4-Tert-octylphenol to Estrogen Receptor
Zhu Jinghan,Xue Qiao,
Zhang Aiqian,
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
Corresponding author: Zhang Aiqian,aqzhang@rcees.ac.cn
CLC number: X171.5
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摘要:对特辛基苯酚(4-tert-octylphenol,PTOP)是一种环境内分泌干扰物。已有研究发现虽然其能够直接与雌激素受体(estrogen receptor,ER)的两种亚型(ERα,ERβ)结合并产生干扰效应，但其结合能力却各不相同，PTOP对ERβ表现出更强的结合活性。为了探究PTOP与ER结合的分子机制及其对ER两种亚型的选择性机制，本文采用分子动力学模拟对PTOP-ER复合物进行了研究，并利用MM-GBSA方法计算了结合自由能。结果表明，范德华作用是维持PTOP与ER结合的主要驱动力；而极性相互作用的差异是导致PTOP对ERα和ERβ产生选择性结合的重要因素，PTOP与ERα之间的极性溶剂化作用阻碍了两者的结合。将PTOP与ER的天然底物雌二醇进行比较，发现PTOP与ER口袋之间缺乏氢键稳定二者结合，因此PTOP的结合活性较低。计算模拟亦指出了PTOP结合过程中氨基酸。以上计算结果将有助于我们进一步理解PTOP影响ER介导生理过程的干扰机制。
关键词: 雌激素受体α/
雌激素受体β/
对特辛基苯酚(PTOP)/
分子动力学/
MM-GBSA
Abstract:4-tert-octylphenol (PTOP) is a typical endocrine disrupting chemical,which can interfere with the transcriptional regulation of estrogen receptor (ER) via direct binding to its both subtypes. The structural basis for the fact that binding affinity of ERβ with PTOP is higher than that of ERα is still unclear. To investigate the ER binding mechanism and the subtype selectivity of PTOP, molecular dynamics combined with MM-GBSA was used to perform computational simulations for the PTOP-ER complex. The results indicated that the van der Waals interaction is the major driving force for the ER binding of PTOP, while the polar interaction, especially polar solvation, dominates the PTOP subtype selectivity. The more intensive the polar interaction becomes, the less stable the PTOP-ER complexes are. In addition, low ER affinity of PTOP, in comparison with estradiol, may be attributed to less hydrogen bonds formed in the PTOP-ER complex. Moreover, the key residues which play important roles in the binding process were revealed. This work provides further understanding of low PTOP induce the ER-mediated endocrine disrupting effect in a ligand-depent manner.
Key words:estrogen receptor α/
estrogen receptor β/
4-tert-octylphenol (PTOP)/
molecular dynamics simulation/
MM-GBSA.
