典型环境PBDEs与人血清白蛋白的相互作用及其构效关系研究

Polybrominated diphenyl ethers (PBDEs) with stronge toxicity, a group of brominated flame retardants, had been used extensively in a variety of consumer goods. It has been received wide attention because recent studies have shown that PBDEs reveal stronge toxicity. In present study, the interaction between PBDEs and human serum albumin (HSA) will be investigated by testing the binding constant, the type of binding force, the number of binding site and the binding distance. The effection of the second structure and conformation of HSA for the interaction between PBDEs and HSA, the mechanism of binding and the binding mode will be studied. The effection of the key residue in activity site of HSA for interaction between PBDEs and HSA will be simulated by 3D computational modeling to develop the molecular mechanism of the transport, distribution, and mechanism. The interaction mode between PBDEs and HSA will be built using molecular docking and molecular dynamics simulation, and the 2/3D-QSAR models will be constructed to predict and assess the binding ability. The simulated and modeling results will be provided usful information to interpret the mechanism of the interaction between PBDEs and HSA from molecular level. Therefore, the potential transport and distribution mechanism of the of PBDEs would be reveal, and that may provid theoretical guidance and precitical experience for pollution prevention of PDBEs.

PBDEs作为一种阻燃剂得到广泛应用。研究发现PBDEs都具有很强的毒性，引起了人们的广泛关注。本研究选取不同溴取代的PBDEs为对象，与人血清蛋白(HSA)进行相互作用实验研究，测定相互作用的结合常数、作用力类型、结合位点数、结合空间距离等参数，探讨HSA二级结构及其构象对与PBDEs结合的影响、相互作用的键合机理和作用模式；以三维方法模拟PBDEs与HSA结合的活性位点残基对其相互作用的影响，从分子水平探究PBDEs在人体内的吸收、传输、分布以及毒理作用的分子机制；以分子对接和分子动力学方法模拟HSA的三维空间结构，建立与PBDEs相互作用的模型，以2/3D-QSAR方法对PBDEs的与HSA的结合能力进行预测和评价，为从分子结构上解析HSA与PBDEs结合能力提供有用的信息。从而揭示PBDEs在生物体的可能的传输、分布等机制；为PBDEs污染防治提供理论指导和实践经验。

1、本课题在原有的研究基础上完善了基于变量相互作用的变量筛选方法，开发了通用变量筛选与建模程序GVSMP、自动优化支持向量机建模参数的软件和从Gaussian 09计算结果中提取量子化学参数的Molcular Descriptor Calculator软件，然后进行应用研究。.2、基于光谱法研究了多溴二苯醚和羟基化多溴二苯醚与人血清白蛋白相互作用机制，从无羟基、羟基位置、溴原子的个数及溴原子的位置四个方面探讨多溴二苯醚和羟基化多溴二苯醚与人血清白蛋白的结合常数、结合类型、结合位置、结合位点数、结合空间距离及其作用力类型；探讨了HSA二级结构及其构象对与PBDEs和OH-PBDEs结合的影响、相互作用的键合机理和作用模式、荧光猝灭类型及能量转移方式。通过分子动力学和分子对接技术模拟了PBDEs和OH-PBDEs与HSA结合的活性位点氨基酸残基对其相互作用的影响及作用模型，从分子水平探究PBDEs 在人体内的吸收、传输、分布以及毒理作用的分子机制。采用2/3D-QSAR 方法研究了PBDEs与HSA 的结合能力进行预测和评价，为从分子结构上解析HSA 与PBDEs 结合能力和揭示PBDEs 在生物体的可能的传输、分布等机制提供了有用的信息。同时也研究了四种酞酸酯、几种多氯联苯和多种全氟化合物与人血清白蛋白（HSA）之间的相互作用。