Yang Xianhai, Lyakurwa Felichesmi, Xie Hongbin, Chen Jingwen, Li Xuehua, Qiao Xianliang, Cai Xiyun
Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, China; Nanjing Institute of Environmental Science, Ministry of Environmental Protection, Nanjing 210042, China.
Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, China.
Chemosphere. 2017 Sep;182:574-583. doi: 10.1016/j.chemosphere.2017.05.016. Epub 2017 May 5.
Chemical forms-dependent binding interactions between phenolic compounds and human transthyretin (hTTR) have been elaborated previously. However, it is not known whether the binding interactions between ionizable halogenated alphatic compounds and hTTR also have the same manner. In this study, poly-/perfluorinated chemicals (PFCs) were selected as model compounds and molecular dynamic simulation was performed to investigate the binding mechanisms between PFCs and hTTR. Results show the binding interactions between the halogenated aliphatic compounds and hTTR are related to the chemical forms. The ionized groups of PFCs can form electrostatic interactions with the -NH groups of Lys 15 residues in hTTR and form hydrogen bonds with the residues of hTTR. By analyzing the molecular orbital energies of PFCs, we also found that the anionic groups (nucleophile) in PFCs could form electron donor - acceptor interactions with the -NH groups (electrophile) in Lys 15. The aforementioned orientational interactions make the ionized groups of the PFCs point toward the entry port of the binding site. The roles of fluorine atoms in the binding interactions were also explored. The fluorine atoms can influence the binding interactions via inductive effects. Appropriate molecular descriptors were selected to characterize these interactions, and two quantitative structure-activity relationship models were developed.
酚类化合物与人转甲状腺素蛋白（hTTR）之间基于化学形态的结合相互作用此前已有阐述。然而，尚不清楚可电离的卤代脂肪族化合物与hTTR之间的结合相互作用是否也具有相同方式。在本研究中，选择多氟/全氟化合物（PFCs）作为模型化合物，并进行分子动力学模拟以研究PFCs与hTTR之间的结合机制。结果表明，卤代脂肪族化合物与hTTR之间的结合相互作用与化学形态有关。PFCs的电离基团可与hTTR中Lys 15残基的-NH基团形成静电相互作用，并与hTTR的残基形成氢键。通过分析PFCs的分子轨道能量，我们还发现PFCs中的阴离子基团（亲核试剂）可与Lys 15中的-NH基团（亲电试剂）形成电子供体-受体相互作用。上述取向相互作用使PFCs的电离基团指向结合位点的入口。还探讨了氟原子在结合相互作用中的作用。氟原子可通过诱导效应影响结合相互作用。选择了合适的分子描述符来表征这些相互作用，并建立了两个定量构效关系模型。
