基于噬菌体尾突蛋白和O抗原弱相互作用的特异性识别分子模拟研究

蛋白质与糖的特异性识别在生命体的信息传递、免疫应答等过程中均发挥关键作用，而目前的研究深度和进展却远未达到人们根据其重要性所作出的预期。由于糖的结构复杂程度远远高于蛋白质等其它生物分子，且蛋白质与糖的相互作用相对较弱，这对现有实验方法和计算机模拟策略设计来说是巨大挑战。从分子尺度理解糖链全局结构与蛋白质-糖相互作用的关系是理解特异性识别的关键。我们在前期工作中选取噬菌体尾突蛋白与单一血清型O抗原片段为研究对象，运用分子动力学模拟方法，对针对糖分子的特定力场参数和系统研究策略进行探索，成功对糖链长度的研究范围作了一定拓展。本项目拟基于前期研究基础，构建系列不同链长、不同血清型O抗原的全原子模型，从糖结构出发解释蛋白–糖这种弱相互作用模式下的特异性识别机理，解释糖分子链长和支链修饰对特异性识别的影响，为蛋白–糖复合物研究提供普适性策略，为相关多糖疫苗设计研发提供关键思路。

Specific recognition of carbohydrates with proteins is essential for many vital processes in biology, such as cell-cell recognition and immune response. Despite the ubiquitous importance of these processes, their underlying molecular details are poorly understood. As a consequence of the incredible diversity of carbohydrates and the weak affinity between proteins and carbohydrates, it is a general challenge for both experimentalists and theorists to investigate the protein-carbohydrate complex. For the example of Shigella flexneri O-antigen polysaccharides, which can be specifically recognized by the bacteriophage tailspike protein, in our recent work we have been able to suggest the binding modes of longer fragments through molecular simulation. Within this project we will investigate the molecular mechanism of weak-affinity specific recognition between tailspike protein and O-antigen fragments by means of state-of-the-art molecular simulation techniques. We aim to explain the origins of differences in specificity of recognition based on the conformational diversity of the carbohydrates with different length and serotypes. This study will suggest a general strategy for investigating molecular details of protein-carbohydrates (with repeating units) complex, which sheds light on design of carbohydrate-based vaccines.