The broad objective of this project is the development and application of a combined nuclear magnetic resonance (NMR) - computational approach to the structural characterization of cell surface oligosaccharides. The oligosaccharides of membrane glycolipids and glycoproteins comprise a diverse set of structures that are hypothesized to play roles in membrane surface reception, differentiation, and functionalization. They serve as receptors for bacterial toxins, viral proteins, and naturally occurring hormones. They serve as markers for differentiating cells during normal and abnormal development. And, the charged, sialic acid containing, oligosaccharides seem to play a role in the modulation of Ca2+ levels near membrane surfaces. Along with a basic understanding of membrane surface properties, a knowledge of the three dimensional structure of these moieties could provide an important basis for the design of agents which more effectively target cells or pathogenic agents which rely on oligosaccharides for recognition. Structural data will be acquired in solution, and in membrane-like phases, on a series of simple glycolipids that include the sialic acid containing gangliosides. The solution studies employ conventional two-dimensional NMR methods that yield structural information through their sensitivity to inter-proton distances, but they also include the development and application of methods that are particularly useful in the location of ion binding sites. The studies in membrane-like environments employ 2H, 1H, and 13C NMR experiments to obtain orientational information from quadrupolar and dipolar couplings. A molecular modeling protocol will be developed that integrates both types of experimental data with molecular energy calculations to provide descriptions of the structure and dynamics of the molecules under study.
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