外膜蛋白组装复合体（Bam）结构与功能的综合计算研究

项目名称： 外膜蛋白组装复合体（Bam）结构与功能的综合计算研究

项目编号： No.31270758

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 田圃

作者单位： 吉林大学

项目金额： 80万元

中文摘要： 杂聚膜蛋白复合体承担着细胞内外特定物质输运和信号传导的功能，也是众多现有药物和新药开发的靶点。由于它们结构不对称的特点和高精度结构实验解析的困难，人们对其结构及功能的了解远远不能和它们在生物医药科学中的重要性匹配。由外膜蛋白组装复合体BAM组装的很多外膜蛋白都与细菌的生理、致病和抗药性有着紧密联系，理清其工作机理对开发新一代抗生素有重要意义。本研究将以Bam组成蛋白的高精度实验结构为基础，对它们的构象空间进行详细的分析，结合现有组成蛋白间相互作用的实验数据，通过基于构象组的蛋白对接建立该复合体的结构模型，提出并且由合作方实验验证特定的蛋白质相互作用位点和关键构象变化，在此基础上进一步完善结构模型，研究该复合体和底物EspP、OmpT及分子伴侣SurA之间的相互作用，对目前假设的各种Bam工作机理进行评价，揭示其完成外膜蛋白组装尚未被发现的可能机理，提出比较完整的Bam功能模型。

中文关键词： 外膜蛋白组装复合体；分子动力学模拟；构象空间离散化；非线性关联；自由能

英文摘要： Hetero-oligomeric membrane protein complexes carry out transport of specific molecules and signals across cell membranes(walls), and are targetted by many drugs on the market and in the development. Structural assymetry of these systems and the difficulty in solving high resolution structures for complete complexes severely impeding our mechanistic understanding of them. Consequently, the current knowledge on the structure and function of these systems is far away from matching their importance in biomedical sciences. Many outer membrane proteins (OMPs) assembled by the Bam(Beta barrel assembly machinery)complex are critical in physiology, pathogenesis and drug resistance of gram-negative bacteria, therefore, understanding the mechanism of OMP assembly by Bam is of great significance in development of next generation antibiotics in particular, and in advancing our knowledge of hetero-oligomeric membrane protein complexes in general. In this study, we plan to first carry out detailed conformational analysis for important comprising proteins that have high resolution experimental structures (BamA,B,D,E) available. With the help of the experimental data restraints, important conformers obtained for comprising proteins will be utilized to propose structural model for the complex based upon extensive docking studies.

英文关键词： Bam molecular system；molecular dynamics simulation；configurational space discretization；nonlinear correlation；free energy