中文摘要：

1,1-二氯-2,2-双（对氯苯基）乙烯（p,p＇-DDE）是一种已知的雄激素受体（androgen receptor,AR）拮抗剂。有趣的是,已有研究证实p,p＇-DDE同时可经由作用于AR的2种天然突变体H874Y和T877A产生拟雄激素效应,但其相互作用的分子机制尚不清晰。本研究联用分子动力学模拟与MM-GBSA方法,以内源性激素二氢睾酮（DHT）作为对照,对p,p＇-DDE与2种突变体的相互作用分子机制进行了研究。模拟结果指出范德华相互作用是维持p,p＇-DDE与AR突变体结合的主要驱动力,而溶剂化作用的差异是导致p,p＇-DDE与H874Y具有较高结合活性的主要原因,H874Y结合口袋与p,p＇-DDE的结构匹配度优于与T877A。与内源性配体二氢睾酮相比较,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的稳定。MM-GBSA的结果确定p,p＇-DDE与突变体结合过程的关键氨基酸以疏水性残基为主,其中L704、M745、L873尤为重要。计算获得的p,p＇-DDE对H874Y及T877A相互作用分子机制有助于理解该污染物在不同人群中内分泌干扰效应的差异。

英文摘要：

1,1-dichloro-2,2-bis（p-chlorophenyl）ethylene （p,p＇-DDE） as a typical androgen receptor （AR） antagonist exhibits agonism effect on AR mutants H874Y or T877A. The structural basis for agonism mechanisms of p,p＇- DDE via H874Y/T877A is still unclear. Thus, molecular dynamics （MD） simulations combined with MM-GBSA was used to perform computational calculations for exploring the interaction features ofp,p＇-DDE-AR mutant complex. The result is consistent with the reported experiment. The Van der Waals interaction is found to be the predominant driving force facilitating the complex stability. Compared with T877A, H874Y presents a higher binding activity with p,p ＇-DDE due to its favorable solvation effect, and its binding pocket fits p,p＇-DDE better than T877A. In comparison with the endogenous ligand dihydrotestosterone, p,p＇-DDE shows lower mutant binding af- finity because of decreased van der Waals energy and electrostatic energy. The lack of hydrogen bonds between p,p＇-DDE and AR-mutants destabilizes 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. The obtained molecular mechanism for the interaction between p,p＇-DDE and the AR mutants provides insight to the cohort effect observed for the health hazard of the pollutant.