Conformational Equilibria of Biologically Relevant Oligosaccharides

在人体内，大约一半的蛋白质都是由糖修饰的。这些混合结构被称为糖蛋白。糖蛋白可以在细胞内发现，附着在细胞外表面（细胞膜）或细胞外空间。人们越来越认识到，这些糖蛋白的糖成分在人类健康和疾病中起着至关重要的作用，例如，在细菌和病毒感染、癌症、免疫和糖尿病中。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，它们在三维空间中的行为，以及它们的形状如何随时间变化。该项目将开发新的分析工具来研究和分配溶液中的糖结构。学生将接受实验和理论方法的交叉训练，从糖的化学合成到用于预测其分子结构的先进计算方法。这项工作的目的是在实验和理论之间提供新的串扰，目的是将两者提炼成更强大的工具来理解糖蛋白结构。有了这个奖项，化学部门的生命过程化学项目和计算与数据支持科学与工程项目将资助博士。圣母大学的Anthony Serianni和Ian Carmichael，以及佐治亚大学的Robert Woods博士，共同开发新的核磁共振（NMR）光谱和计算工具，以预测人类糖蛋白的高甘露糖和复杂型n -聚糖的三维结构和动力学。本研究小组将使用冗余核磁共振j偶联来实验确定这些n -聚糖中包含o -糖苷键的可旋转键的构象居群。为了实现这一目标，将使用计算方法（密度泛函理论）来推导新的方程，这些方程将特定j型联轴器的大小与连杆中的特定扭转角联系起来。利用新的构象居群实验数据，将实验结果与从溶剂化分子动力学模拟中获得的理论构象居群进行比较，以验证MD方法的预测或证明对MD方法基础方程的修改。长期目标是确定生物学上重要的复杂寡糖的详细结构特性，无论是在溶液中游离还是与蛋白质或脂质结合。这些知识将证明对理解n -聚糖如何发挥其无数的生物学功能是有价值的。

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.