Conformational Equilibria of Biologically Relevant Oligosaccharides

生物学相关寡糖的构象平衡

• 批准号: 1402744
• 负责人: Anthony Serianni
• 金额: $ 75万
• 依托单位: University of Notre Dame
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1402744&HistoricalAwards=false
• 关键词: Conformational; Equilibria; Biologically; Relevant; Oligosaccharides

In the human body, approximately half of all proteins are decorated with sugars. These hybrid structures are known as glycoproteins. Glycoproteins can be found inside cells, attached to their external surfaces (cell membranes) or in the extracellular space. There is increasing appreciation that the sugar component of these glycoproteins plays a crucial role in human health and disease, for example, in bacterial and viral infection, cancer, immunity, and diabetes. Efforts to understand these cellular processes depend upon knowledge of the chemical structures of the sugars on the protein, that is, what sugars are present, how they behave in three dimensions, and how their shapes change over time. This project will develop new analytical tools to investigate and assign sugar structure in solution. Students will be cross-trained in both experimental and theoretical methods ranging from chemical synthesis of sugars to advanced computational methods used to predict their molecular structures. The work aims to provide new crosstalk between experiment and theory, with the intent of refining both into more powerful tools to understand glycoprotein structure.With this award, the Chemistry of Life Processes Program in the Chemistry Division and the Computational and Data-Enabled Sciences and Engineering Program is funding Drs. Anthony Serianni and Ian Carmichael of the University of Notre Dame, and Dr. Robert Woods of the University of Georgia, to develop new nuclear magnetic resonance (NMR) spectroscopy and computational tools to predict the three-dimensional structures and dynamics of the high-mannose and complex-type N-glycans of human glycoproteins. This research group will use redundant NMR J-couplings to experimentally determine conformational populations about the rotatable bonds comprising the O-glycosidic linkages in these N-glycans. To achieve this goal, computational methods (density functional theory) will be used to derive new equations that relate the magnitudes of specific J-couplings to specific torsion angles in the linkages. Armed with new experimental data on conformational populations, comparisons will be made between the experimental findings and theoretical conformational populations obtained from solvated molecular dynamics simulations, in an effort to validate the MD predictions or justify modifications in the equations underlying the MD method. The long-term goal is to determine the detailed structural properties of biologically important complex oligosaccharides, either free in solution or bound to proteins or lipids. This knowledge will prove valuable in understanding how N-glycans exert their myriad biological functions.

在人体内，大约一半的蛋白质是由糖装饰的。这些杂合结构被称为糖蛋白。糖蛋白可以在细胞内、附着在细胞外表面(细胞膜)或细胞外空间中找到。人们越来越认识到，这些糖蛋白中的糖成分在人类健康和疾病中发挥着关键作用，例如在细菌和病毒感染、癌症、免疫和糖尿病方面。理解这些细胞过程的努力取决于对蛋白质上糖的化学结构的了解，也就是说，存在什么糖，它们在三维中的表现，以及它们的形状如何随着时间的推移而变化。该项目将开发新的分析工具来研究和指认溶液中的糖结构。学生将在实验和理论方法方面进行交叉培训，范围从糖的化学合成到用于预测其分子结构的先进计算方法。这项工作旨在提供实验和理论之间的新串扰，目的是将两者提炼成更强大的工具来了解糖蛋白结构。凭借这一奖项，化学系的生命过程化学计划以及计算和数据启用的科学与工程计划将资助圣母大学的Anthony Serianni博士和Ian Carmichael博士以及佐治亚大学的Robert Wood博士开发新的核磁共振(核磁共振)波谱和计算工具，以预测人糖蛋白的高甘露糖和复合型N-糖聚糖的三维结构和动力学。这个研究小组将使用冗余的核磁共振J-偶联来实验地确定这些N-糖链中包含O-糖苷键的旋转键的构象布居。为了实现这一目标，将使用计算方法(密度泛函理论)推导出将特定J联轴器的大小与连杆中特定扭转角联系起来的新方程。利用构象布居的新实验数据，将实验结果与溶剂化分子动力学模拟得到的理论构象布居进行比较，以验证MD预测或证明MD方法所依据的方程的修改是合理的。长期目标是确定具有生物重要性的复杂低聚糖的详细结构属性，这些低聚糖要么在溶液中自由存在，要么与蛋白质或脂类结合。这些知识将被证明对理解N-葡聚糖如何发挥其无数的生物学功能是有价值的。