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| 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 | |
| 其他题名 | Theoretical Study on Molecular Mechanism for Interaction between PTOP/p,p’-DDE and Typical Hormone Receptors |
| 朱婧涵 | |
| 出版年 | 2017 |
| 学位类型 | 硕士 |
| 导师 | 张爱茜 |
| 学位授予单位 | 中国科学院大学 |
| 中文摘要 | 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。 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；MM-GBSA |
| 英文摘要 | ABSTRACTNowadays 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 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. Keywords: estrogen receptor subtype, androgen receptor mutant, environmnetal endocrine disruptors, molecular dynamics simulation, MM-GBSA |
| 中文关键词 | 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 ; MM-GBSA |
| 英文关键词 | estrogen receptor subtype androgen receptor mutant environmnetal endocrine disruptors molecular dynamics simulation MM-GBSA |
| 语种 | 中文 |
| 国家 | 中国 |
| 来源学科分类 | 环境科学 |
| 来源机构 | 中国科学院生态环境研究中心 |
| 资源类型 | 学位论文 |
| 条目标识符 | http://119.78.100.177/qdio/handle/2XILL650/287910 |
| 推荐引用方式 GB/T 7714 | 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]. 中国科学院大学,2017. |
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