Conformational Equilibria of Biologically Relevant Oligosaccharides

化学部的生命过程化学项目正在资助圣母大学的Anthony Serianni教授研究溶液中糖分子的三维形状。除了营养价值，糖在生物学中还扮演着许多其他重要角色。例如，它们附着在细胞的外部，就像细胞-细胞识别的识别码一样。识别依赖于分子在细胞表面的特定形状。它们就像拼图一样拼合在一起。脱氧核糖核酸（DNA）和蛋白质分子的形状是常规确定的，但糖的结构迄今为止尚无解决方案。本研究的目标是在实验和理论的基础上发现一种测定溶液中糖结构的通用方法。当实验结构与理论结构相匹配时，就有信心得到了正确的形状。这种新方法完全是通用的，适用于任何溶液中的糖。在实验和计算科学方面有兴趣和专业知识的高级研究员、博士后、研究生和本科生合作实现项目目标。Serianni教授的研究成果已在他于1982年共同创立的Omicron Biochemicals， Inc.商业化。欧米克隆根据新的反应制备糖及其衍生物。这些糖用于基础化学、生物化学和生物学研究、生物医学和临床研究以及诊断工具的开发。Omicron定期与巴黎圣母院的Serianni教授实验室合作，提供合成专业知识和试剂，以支持糖化学和生物化学的基础和应用研究。本课题采用稳定同位素标记的低聚糖，核磁共振（NMR）自旋耦合，密度泛函理论计算和循环统计来确定溶液中低聚糖柔性结构域的构象居群。这种实验方法是可能的，因为糖含有多个冗余的NMR自旋偶联，报告相同的构象域，允许定量处理产生种群模型。根据不同的领域，测试了单状态和多状态模型。一旦给定的结构域被参数化（例如，一个o -糖苷键），它的构象性质就会在不同的结构背景下进行研究，以确定它对环境信号的构象适应程度。实验推导的模型与分子动力学模拟得到的模型进行了比较，以验证后者。这项工作可能会导致新的基于实验的低聚糖中o -糖苷键的构象分类，并更深入地了解影响低聚糖在溶液中构象的多种因素。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Anthony Serianni from the University of Notre Dame to investigate the three-dimensional shape of sugar molecules in solution. Beyond their nutritional value, sugars play numerous other critical roles in biology. For example, they are attached to the outside of cells like an identification number for cell-cell recognition. Recognition depends on the specific shapes the molecules adopt on the cell surface. They fit together much like the pieces of a puzzle. The shapes of deoxyribonucleic acid (DNA) and protein molecules are determined routinely, but sugar structures defy solution so far. The research targets the discovery of a general method for the determination of sugar structures in solution based on both experiments and theory. When the experimental structures match the theoretical ones, there is confidence that the shape is obtained correctly. This new approach is entirely general, applicable to any sugar in solution. Senior investigators, postdoctoral fellows, graduate students and undergraduates with interests and expertise in experimental and computational science collaborate to achieve the goals of the project. Research by Professor Serianni has been commercialized at Omicron Biochemicals, Inc., which he cofounded in 1982. Omicron prepares sugars and their derivatives based on novel reactions. These sugars are used in fundamental chemical, biochemical and biological research, in biomedical and clinical studies, and in the development of diagnostic tools. Omicron regularly collaborates with the Professor Serianni's laboratory at Notre Dame by providing synthetic expertise and reagents to support fundamental and applied studies of sugar chemistry and biochemistry.This research project uses stable isotopically labeled oligosaccharides, nuclear magnetic resonance (NMR) spin-couplings, and density functional theory calculations and circular statistics to determine conformational populations of the flexible domains of oligosaccharides in solution. This experimental approach is possible because saccharides contain multiple redundant NMR spin-couplings that report on the same conformational domain, allowing quantitative treatments that yield populational models. Depending on the domain, single- and multi-state models are tested. Once a given domain is parameterized (e.g., an O-glycosidic linkage), its conformational properties are investigated in different structural contexts to determine the degree to which it adapts conformationally to environmental cues. Experimentally-derived models are compared to those obtained from molecular dynamics simulations to validate the latter. This work may lead to new experiment-based conformational classifications of O-glycosidic linkages in oligosaccharides, and to a deeper understanding of the multiple factors that influence oligosaccharide conformation in solution.