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题名: 对特辛基苯酚及 p,p׳-DDE与典型激素受体作用机制的理论研究
作者: 朱婧涵1
学位类别: 硕士
答辩日期: 2017-05
授予单位: 中国科学院大学
授予地点: 北京
导师: 张爱茜
关键词: 雌激素受体亚型 ; 雄激素受体突变体 ; 内分泌干扰物 ; 分子动力学 ; estrogen receptor subtype, androgen receptor mutant, endocrinedisrupting chemicals, molecular dynamics simulation, MM-GBSA
其他题名: Theoretical Study on Molecular Mechanism for Interaction between PTOP/p,p׳-DDE and Typical Hormone Receptors
学位专业: 环境科学
中文摘要: 环境污染问题是当今世界共同关心的重大课题。实际面临的环境问题从区域 性、范围小的污染问题逐渐变成了危害不可预见、过程不可逆、规模全球化的环 境问题,甚至威胁到人类的生存和繁衍,例如全球变暖、酸雨、水资源危机、土 地荒漠化和有毒化学品污染等。其中,一类长期对人类和其他生物体产生不良影 响却曾长期被忽视的污染因素—内分泌干扰物 (Endocrine Disrupting Chemicals, EDCs)已经引起科学界的关注与重视。EDCs是一类广泛分布于环境中,通过饮 食摄入、皮肤吸收等多种途径进入生物体内发生生物积累,能够模拟天然激素来 破坏机体内分泌等系统的调节功能,对机体的内分泌、生殖等系统造成严重影响 的环境污染物。EDCs与人类的一些疾病密切相关,现已成为环境科学、毒理学、 生物学等领域的研究热点。 许多研究表明,EDCs能够与激素受体家族成员相互作用,破坏正常的天然 激素代谢,干扰其介导的信号通路发生异常转录激活或抑制,进而影响受体蛋白 所介导的正常生理过程,以痕量便可对人体和野生动物产生巨大的危害。本论文 选择两种典型的 EDCs,即对特辛基苯酚(4-tert-octylphenol, PTOP)和 1,1-二氯-2,2- 双(对氯苯基)乙烯(p,p׳-DDE)为研究对象,分别选用雌激素受体(Estrogen Receptor, ER)的两种亚型(ERα, ERβ)和雄激素受体(Androgen Receptor, AR)的两种突变体 (H874Y, T877A)作为目标受体,联用分子动力学模拟与 MM-GBSA方法,开展 EDCs拟雌/雄激素效应分子机制的理论研究。以上研究可有助于人们从原子层面 理解 EDCs影响人体典型激素受体介导生理过程的干扰机制,认识亚型差异所致 生物学效应组织/器官差异的结构基础,理解同一污染物经由同一种受体所致毒 性的人群敏感性不同的分子机制,为 EDCs的生态和健康风险评价提供理论指导 和方法依据。本论文的主要研究内容分为以下两部分: (1)对特辛基苯酚干扰雌激素受体两种亚型介导生物学效应的结构基础 PTOP是一种典型的环境拟雌激素,它能够经由作用于 ER的两种亚型(ERα 和 ERβ)产生拟雌激素效应,但却对 ERβ表现出更强的结合活性。目前,PTOP 对 ER在分子层面的干扰机制及其对 ERβ的选择性结合机制尚不清楚。实验采用 分子对接、分子动力学模拟并结合 MM-GBSA方法,以内源性激素雌二醇 E2为 对照,对 PTOP与 ER两种亚型之间的相互作用分子机制进行了研究。结果表明, 范德华作用是维持 PTOP与 ER结合的主要驱动力;极性相互作用的差异是导致 PTOP与 ERβ具有较高结合活性的主要原因。与 E2相比较,PTOP与 ER口袋之 间缺乏氢键稳定二者的结合,造成 PTOP比 E2的结合活性低。MM-GBSA的结 果确定了 PTOP与 ER结合的重要氨基酸,其中 ERα的 L346(ERβ中的相应残 基编号为 L298)、A350(302)、L387(339)、L391(343)和 F404(356)对识别与结合 小分子尤为重要。 (2)p,p'-DDE活化雄激素受体突变体 H874Y和 T877A的分子机制 p,p'-DDE是一种已知的雄激素受体拮抗剂。已有研究证实 p,p'-DDE可经由 作用于 AR两种天然突变体 H874Y和 T877A产生拟雄激素效应,并对 H874Y 表现出更强的结合活性,但目前关于 p,p'-DDE活化 H874Y和 T877A的分子机 制及其转录活化性能差异的结构基础缺乏原子层面的认识。本研究联用分子对接、 分子动力学模拟与 MM-GBSA方法,以内源性激素二氢睾酮 DHT作为对照,对 p,p'-DDE与两种突变体的相互作用分子机制进行了研究。模拟结果表明,范德华 相互作用是维持 p,p'-DDE与 AR两种突变体结合的主要驱动力。溶剂化作用的 差异是导致 p,p'-DDE对 H874Y表现出较高亲和性的主要原因,H874Y结合口袋 与 p,p'-DDE的结构匹配度优于与 T877A。与 DHT相比较,范德华作用与静电相 互作用的差异是造成 p,p'-DDE比 DHT结合活性低的主要原因;p,p'-DDE与 AR 突变体之间缺乏氢键稳定二者的结合,造成 p,p'-DDE比 DHT的结合活性低。计 算模拟亦指出了 p,p'-DDE与突变体结合过程中发挥重要作用的关键氨基酸主要 为疏水性残基,其中 L704、M745、L873对结合有非常显著的能量贡献。
英文摘要: Nowadays environmental pollution is a major issue of common concern in the world. Many environmental problems such as global warming, acid rain, water crisis, land desertification and toxic chemical pollution, are irreversible and global issues not only regional troubles, which threatened the survival of mankind. In recent years, more attention has already been paid on the ecological and health risk of environmental endocrine disruptors (EDCs), a kind of pollutants exerting harmful biological effect through interrupting hormone related physiological process, whose damage has ever been underestimated for a long time. As chemical contaminants, EDCs are ubiquitous in the environment, and there are multiple pathways of EDCs exposure like dietary and dermal exposure. EDCs have been reported to mimic the behavior of endogenous hormones to induce disorders in especially endocrine system and reproductive system. Because of their close relation to various human diseases, EDCs have become a hot research area in different disciplines such as environmental science, toxicology and biology. Many studies have shown that EDCs can interfere with the transcriptional regulation of hormone receptors, are associated with abnormal transcription activation or suppression of the receptors, and thus may affect the receptor-mediated endocrine disrupting effects via direct receptor binding. In the present study, two typical EDCs, 4-tert-octylphenol(PTOP)and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), were selected as pollutant templates, while estrogen receptor (ER) and andtogen receptor (AR), which are the biomarkers for breast cancer and prostate cancer, respectively, were used as target proteins. Molecular dynamics simulation analysis coupled with MM-GBSA calculations was adopted to elucidate the molecular mechanism of estrogenic and androgenic effect for PTOP and p,p'-DDE. Specifically, in order to clarify the structural basis for subtype-based tissue/organ difference in ER-mediated effects and delineate the potential rule for the population susceptibility to the EDCs-related body damage, the exploration has been focused on the molecular recognition and receptor selectivity of two ER subtypes, ERα and ERβ, and two AR mutants, H874Y and T877A The major content of the work is as follows. 1. Structural basis and molecular mechanism for selective binding of 4-tert-octylphenol to ERβ PTOP is a typical EDCs which can interfere with the transcriptional regulation of two ER subtypes via direct binding, but the structural basis for the fact that PTOP has a higher binding affinity with ERβ than ERα is still unclear. ER binding mechanism and the subtype selectivity of PTOP were investigated by docking analysis and molecular dynamics simulation combined with MM-GBSA calculations. 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. In comparison with the endogenous ligand estradiol, PTOP shows lower binding affinity because of the lack of hydrogen bonds established between PTOP and ER. Moreover, the key residues which play essential roles in the binding process were revealed, in which L346(L298 in ERβ), A350(302), L387(339), L391(343) and F404(356) are particularly important to identify and interact with small molecules. 2. Agonism mechanism of p,p'-DDE via interacting with androgen receptor mutants H874Y and T877A p,p'-DDE is a typical AR antagonist but exhibits agonism effect on AR mutants H874Y or T877A. Moreover, p,p'-DDE shows stronger binding activity to H874Y than to T877A. In this study, molecular docking and molecular dynamics(MD) similations combined with MM-GBSA were used to perform computational analysis to explore the interaction features of p,p'-DDE with AR mutants. The result is consistent with the reported experimental findings. The Van der Waals interaction is found to be the predominant driving force facilitating the complex stablity. Compared with T877A, H874Y presents a higher binding activity of p,p'-DDE due to its favorable solvation effect, and its binding pocket fit p,p'-DDE better than that of T877A. In comparison with the endogenous ligand dihydrotestosterone, p,p'-DDE shows lower mutant binding affinity because of decreased van der Waals energy and electrostatic energy. The lack of hydrogen bonds between p,p'-DDE and AR-mutants The major content of the work is as follows. destabilize the interaction between p,p'-DDE and AR mutants. Moreover, the result of MM-GBSA identifies the key residues between p,p'-DDE and AR mutants. Nonpolar residues in the binding pocket, especially L704, M745 and L873, play important roles in the binding process.
内容类型: 学位论文
URI标识: http://ir.rcees.ac.cn/handle/311016/38762
Appears in Collections:环境化学与生态毒理学国家重点实验室_学位论文

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作者单位: 1.中国科学院生态环境研究中心

Recommended Citation:
朱婧涵. 对特辛基苯酚及 p,p׳-DDE与典型激素受体作用机制的理论研究[D]. 北京. 中国科学院大学. 2017.
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