Conformational Equilibria of Biologically Relevant Oligosaccharides

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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.