卤代酚类有机污染物与甲状腺蛋白作用的分子机制研究

Studies have found that Phenolic Organohalogens (POH) pollutants have highly toxicity and have attracted widespread attention from researchers and regulatory agencies. In this study, different POHs were used as targets to study the binding of thyroid transporters (TTR) and thyroxine-binding globulin (TBG). Multi-spectral methods will be used to test the parameters of POH binding to TTR/TBG, such as binding ability, types of interaction forces, number of binding sites, spatial distances. And then, the effect of secondary structure and its conformation on the binding of TTR/TBG to POH, the binding mechanism and the mode of action will be to explore. The possible mechanism of the interaction between POH and TTR/TBG will be studied from the molecular level by computational simulation. The 2/3D-QSAR models will be constructed to predict and assess the binding ability of POH bind to TTR/TBG. The simulated and modeling results will provide useful information to interpret the mechanism of the interaction between POH and TTR/TBG from molecular level, and that may provide theoretical guidance and practical experience for pollution prevention of POH.

研究发现卤代酚类有机污染物（POH）都具有很强的毒性，已经引起了研究者和管理部门的广泛关注。本研究以不同POH为对象，与甲状腺转运蛋白（TTR）和甲状腺素结合球蛋白（TBG）进行结合作用研究，采用多光谱方法测定其结合能力、作用力类型、结合位点、结合空间距离等参数，探讨二级结构及其构象对TTR/TBG与POH结合的影响、结合机理和作用模式；结合计算模拟方法研究POH与TTR/TBG结合可能的作用模式，从分子层面探究POH与TTR/TBG结合作用的可能作用机制；构建2/3D-QSAR模型对POH与TTR/TBG的结合能力进行评价和预测，为从分子结构上解析TTR/TBG与POH结合能力提供有用的信息。从而为揭示POH在生物体产生危害的可能机制提供参考；为POH的对甲状腺系统危害防治提供理论指导和实践经验。

采用分子对接、分子动力学模拟和多光谱技术（紫外、分子荧光和红外光谱等）研究了部分OH-PBDEs、OH-PCBs、卤代双酚、卤代苯酚、卤代苯硫酚等卤代酚类有机污染物与甲状腺蛋白的结合机制。主要内容包括：（1）通过荧光光谱研究了卤代酚类有机污染物与甲状腺蛋白的结合能力、结合位点作用力类型、结合距离结合常数以及小分子结合对甲状腺蛋白构象变化的影响等；（2）采用紫外与荧光光谱结合研究了卤代酚与蛋白结合后荧光猝灭机制；（3）通过红外光谱探讨了卤代酚与蛋白结合后的二级结构影响情况；（4）并应用分子对接、分子动力学模拟、量子化学计算对结合位点活性残基、构象变化、电荷变化、分子间作用力等进行分析从分子水平对蛋白与卤代酚类有机污染物结合作用机制进行了探讨。研究结果为从分子结构上解析卤代酚类有机污染物与甲状腺蛋白结合性能和分子机制提供了有用的信息。