结合分子模拟和网络方法分析β2肾上腺素受体激活过程的构象变化  

A Combination of Molecular Simulation and Network Methods for Analysis of Conformation Variation in Activation Process of β2 Adrenergic Receptor

作　　者：肖秀婵[1] 华勇攀 高楠[1] 江源远[1] 蒲雪梅[1] 李梦龙[1] 

机构地区：[1]四川大学化学学院,成都610064 [2]四川大学计算机学院,成都610064

出　　处：《分析化学》2015年第11期1722-1727,共6页Chinese Journal of Analytical Chemistry

基　　金：国家自然科学基金(No.21273154)资助~~

摘　　要：顺应蛋白质结构功能研究的发展对构象信息的需求,结合靶向分子动力学模拟和蛋白质网络方法建立了对β2肾上腺素受体激活信号传导相关的构象变化的解析方法,通过分子动力学模拟获取激活过程的构象集合,并进一步采用网络分析方法去识别构象变化过程中的关键残基及关键路径。结果表明,β2肾上腺素受体构象变化是各个区域之间信号传递的综合,跨膜螺旋的连接区域是信号传递的枢纽,螺旋两端包括胞内外Loop区域是信号传导的核心区域。关键路径分析发现,信号传递通路不止一条,都是从配体结合口袋残基Ser204附近开始,分别传递到NPxx Y区域和ICL2区域,其中螺旋Ⅲ,Ⅴ,Ⅵ是信号传递的必经区域,这些研究成果为β2AR激活信号传导过程的阐明提供了重要的分子信息。To fill the urgent need of researches on the structure and function of proteins to obtain conformation information,we combined targeted molecular dynamics（ TMD） simulation with protein network methods to analyze conformation variations in the activation process of β2 adrenergic receptor. First,targeted MD was used to obtain the conformation resembles in the activation process,and then the protein network method was applied to identify the key residues and pathways in the activation process. The results indicate that the activation process of β2 adrenergic receptor involves in the cooperation of all regions and the connector region of transmembrane helices is signaling hubs. In addition,the helix ends,including intracellular and extracellular loops,are the core areas. The pathway analysis reveals that there is more than one signaling pathway. All the pathways start from Ser204 of the ligand pocket and finally transmit to NPxx Y or ICL2 region,which are depended on the different pathways. While the helix TMIII,TMV,TMVI are the important areas in all the pathways. The observations from the work provide valuable information at molecular level for unraveling the signal transduction mechanism associated with the activation process.

关 键 词：Β2肾上腺素受体 激活过程 构象变化 靶向分子动力学模拟 蛋白质网络 关键残基 

分 类 号：O629.73[理学—有机化学]