Conformational Equilibria of Biologically Relevant Oligosaccharides

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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.