中文摘要：

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结合过程中发挥重要作用的关键氨基酸。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。

英文摘要：

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, dominatesthe 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 how PTOP induce the ER-mediated endocrine disrupting effect in a ligand-depent manner.