基于层级式计算机模拟技术的细菌多糖疫苗高级构象分析的新策略研究

糖科学是精准治疗研究发展的关键领域之一。糖分子参与介导生物体内多种生理病理过程，是一类非常重要的效应分子。由于糖链高度复杂的固有结构，使得其结构分析技术，特别是二级及以上构象分析技术的瓶颈突破困难重重，这导致糖类药物及功能分子的研究热度无法匹配其重要性和紧迫度。目前急需结合多种分析手段发展专门针对糖固有构象的组合策略与方法。随着计算机信息处理和人工智能技术的广泛兴起，计算机辅助药物分析在药物分析特别是复杂药物分析中发挥日益重要的作用。我们在前期工作中采用计算机分子模拟针对具有复杂重复单元的特定血清型细菌疫苗的寡糖结构进行了系统研究。本项目拟基于上述研究，逐级构建适用于不同血清型多种侧链修饰和不同链长的细菌多糖疫苗的精确动态构象样本库，运用层级式构建策略发展具有普适性的粗粒化模型，实现对于具有复杂重复单元的不同侧链修饰的柔性糖链全局构象的快速预测，为具有特异性需求的细菌多糖疫苗设计提供思路。

Glycoscience promotes the achievements in biology and immunology, which plays a key role in the development of precision medicine. As one of the most important groups of the effector in the human body, carbohydrates participate in many physiological and pathological processes in organisms. Due to the super complicated structure of the carbohydrates, their conformational analysis techniques are unfortunately hardly developed, which hindered the sugar-based drug research and design. It is necessary to develop the appropriate strategy which effectively combines multiple analysis techniques for thorough sugar conformation analysis. Currently, the computer-aided drug analysis methods have attracted increasing interest owing to the rapid development of the computer information processing and AI technology. In our previous work we systematically investigated the conformation diversity of a high-rhamnose, serotype Y O-antigen polysaccharide of the Gram-negative bacterium Shigella flexneri as a first step of the issue. In this project, we will investigate the conformational diversity of a series of bacterial polysaccharide with different length and branch by means of multiscale molecular simulation techniques. We aim to build up an accurate database of the investigated sugar dynamic conformation samples in aqueous solution and figure out the key factors pointing to the global conformation changes. This study will suggest a noval strategy for investigating molecular details carbohydrates, which sheds light on design of carbohydrate-based vaccines.