突触素Ⅰ与丙烯酰胺相互作用模式研究  

Mode study on the interaction of synapsin Ⅰ and acrylamide

作　　者：杨义光[1] 陈宵[1] 张意[1] 蔡文健 李忠生[1] 肖经纬[1] 李斌[1] YANG Yi-guang;CHEN Xiao;ZHANG Yi;CAI Wen-jian;LI Zhong-sheng;XIAO Jing-wei;LI Bin(National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China)

机构地区：[1]中国疾病预防控制中心职业卫生与中毒控制所,北京100050

出　　处：《毒理学杂志》2018年第3期173-179,共7页Journal of Toxicology

基　　金：国家自然科学基金(81773474);国家重点研发计划(2017YFF0211201)

摘　　要：目的通过同源模建方法获得突触素Ⅰ蛋白(synapsin Ⅰ,Syn Ⅰ)功能域的三维结构,采用分子对接、分子动力学模拟方法研究小分子丙烯酰胺(acrylamide,ACR)与Syn Ⅰ蛋白相互作用模式及结合位点,提供ACR对Syn Ⅰ蛋白损伤作用机制的证据。方法使用Dock 6.7分子对接程序和Amber Tools15分子动力学模拟程序包进行计算模拟。结果分子对接计算表明ACR和蛋白质间存在3种不同模式(体系Ⅰ、Ⅱ、Ⅲ)。分子动力学模拟将结合模式缩减至2种:小分子以体系Ⅰ方式与蛋白质结合力最强,其中氨基酸残基Asn214、Ser390和Ser391的作用力贡献较为突出;体系Ⅱ、Ⅲ为相同结合模式有异于体系Ⅰ,可能同时存在另一种结合模式,其中Glu373和Lys225的作用较为明显。结果提示,氢键、静电力和范德华力及钙离子(Ca^(2+))对两者的结合具有重要作用。3种模式均致口袋形状增大,Ca^(2+)结合变弱,水溶剂分子更容易进入口袋,为后续化学反应创造环境。结论在分子动力学模拟中,ACR在Ca^(2+)存在条件下与Syn Ⅰ功能域相互作用,体系Ⅰ中结合位点为氨基酸残基Asn214、Ser390和Ser391,体系Ⅱ、Ⅲ的结合位点为氨基酸残基Glu373和Lys225,且Syn Ⅰ蛋白在与小分子结合后构象发生变化。本研究对ACR所致Syn Ⅰ蛋白相关性神经损伤机制的进一步研究具有一定的提示作用。Objective To study the three-dimensional structure of synapsin Ⅰ（ Syn Ⅰ） protein domain by homology modeling and to study the interaction and probable docking sites between small molecule acrylamide（ ACR） and Syn Ⅰ protein by molecular docking and molecular dynamics simulation,which can provide evidences of the mechanism of acrylamide induced-Syn Ⅰ protein damage. Method Docking simulation was carried out using software included Dock 6. 7 and Amber Tools15 molecular dynamics simulation program package.Results Molecular docking calculation showed that three different patterns between ACR and proteins（ system Ⅰ,Ⅱ and Ⅲ） might exist.Molecular dynamics simulation reduced the three patterns to two binding modes： the binding force of Small molecules to protein through system Ⅰ was the strongest,among them,the contribution of amino acid residues Asn214,Ser390 and Ser391 was particularly prominent. System Ⅱ and Ⅲ were of the same binding mode,but different from that of system Ⅰ. So another binding mode might present simultaneously and the effects of Glu373 and Lys225 might be obvious. The simulation result showed that the hydrogen bond,electrostatic force,van der Waals forces and calcium ions played an important role in the combination of the two. All three models resulted in the increase in the shape of the pocket,which weakened the Ca^（2＋）binding and made it easier for aqueous solvent molecules to enter the pocket,creating an environment for subsequent chemical reactions. Conclusion In molecular dynamics simulations,ACR interacts with the Syn Ⅰ domain in the presence of calcium ions. In system Ⅰ,the binding sites were the amino acid residues Asn214,Ser390 and Ser391,and in system Ⅱ and Ⅲ the counterpart were Glu373 and Lys225,and Syn Ⅰ protein conformation changed after binding to small molecules. The research was a guide for the mechanism of nerve injury caused by ACR.

关 键 词：分子对接 分子动力学模拟 丙烯酰胺 突触素Ⅰ 结合模式 

分 类 号：R114[医药卫生—卫生毒理学]