中文摘要：

混合物毒性的评估与预测一直是毒理学和环境科学领域的前沿和热点.浓度加和模型（CA）和独立作用模型（IA）是目前应用最多的2个加和参考模型.但是,由于作用模式的相似性或相异性难以确定,难以在实际工作中选择合适的参考模型.为了探索分子水平上的结合模式与加和模型的关系,本研究以4种1-烷基-3-甲基咪唑氯离子液体（[Cnmim]Cl,n=2,6,8,12）和萤火虫荧光素酶为研究对象,采用分子对接和分子动力学模拟确定离子液体与萤火虫荧光素酶的结合模式,结果表明[C2mim]Cl和[C6mim]Cl与荧光素酶具有相似的结合模式（BP1和BP2）,[C8mim]Cl和[C12mim]Cl具有相同的结合模式（BP3）.通过荧光素酶微板毒性分析法测定4个离子液体及两两组合构成的6个二元混合物体系共18条混合物射线的发光抑制毒性,应用CA和IA模型评估混合物毒性.结果表明,具有不同结合模式的[C2mim]Cl-[C8mim]Cl和[C2mim]Cl-[C12mim]Cl混合物体系,其毒性可用IA预测;具有相同结合模式的[C2mim]Cl-[C6mim]Cl和[C8mim]Cl-[C12mim]Cl体系,其毒性可用CA预测;而[C6mim]Cl-[C8mim]Cl和[C6mim]Cl-[C12mim]Cl体系,其部分混合物毒性可用CA描述,因其组分的结合模式既有相似性又有相异性.

英文摘要：

The evaluation and prediction of mixture toxicity is a hot topic of toxicology and environmental sciences. The Concentration Addition（CA） and Independent action（IA） models are the primary reference models. CA is suitable for predicting the toxicity of the mixture where the components have same mode of action（MOA） and the IA for toxicity of mixture where components have different MOA. Nonetheless, it is very difficult to obtain the information about the MOA of chemicals. Therefore, it is important to explore a feasible and efficient method to identify MOA. In this study, to reveal the mechanisms of toxic action of ionic liquids（ILs） to firefly luciferase and further build the prediction model for mixture toxicity, luciferase is treated as the biomolecular receptor and four 1-alkyl-3-methyl-imidzole chloride ILs（[Cnmim]Cl, ILn, n=2, 6, 8, 12） are treated as the ligands. The binding modes of ligands（ionic liquids） and receptor（luciferase） are identified by molecular docking and molecular dynamics simulations. Molecular dynamics simulations revealed that the imidazolium ring of [C2mim] is bound at the bottom of the luciferin（D-LH2） pocket which is surrounded by Arg218, Phe247 Thr251, Leu286, Arg337, Gly339 and Ile351 and the alkyl-chain extends from the bottom of the pocket to the entrance. The [C6mim] is bound at the pocket which is surrounded by Phe247, Thr251, Gly315, Gly339, Leu342, Ala348 and Ile351. In contrast, the imidazolium ring of [C8mim] and [C12mim] is bound at the entrance of the D-LH2 pocket and the alkyl-chain inserts into the bottom of the D-LH2 pocket, surrounded by Gly200, Arg218, His245, Phe247, Thr251, Gly316, Arg337, Thr343, Leu526 and Thr527. According to the information of the binding site, binding pose, hydrogen bonds and hydrophobic contacts, we can determine whether the ILs have similar binding pattern（BP）. The results show that [C2mim]Cl belongs to BP1 and [C6mim]Cl belongs to BP2. [C8mim]Cl and [C12mim]Cl belong to BP3. We used the firefly luciferase-mi