Carbohydrate Force Field for Molecular Recognition

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Carbohydrates are the most abundant biopolymers on earth. Their biological functions include fuels, energy storage, metabolic intermediates, structural roles and, importantly, molecular recognition, including roles in vaccines, cell-cell recognition and the pathogenic activity of bacterial toxins. Accordingly, detailed knowledge of carbohydrate structure-function relationships would allow for better understanding of a variety of biological phenomena. To explore these structure-function relationships theoretical approaches offer great potential. The proposed study will enhance both our understanding of the structural properties of carbohydrates as well as the utility of theoretical methods in studying carbohydrates, especially those involved in molecular recognition. These goals will be achieved by first investigating the gauche and anomeric effects, known to be important for the conformational properties of mono- and disaccharides, via quantum mechanical (QM) calculations. Information from the QM calculations will lay the groundwork for the development of an empirical force field for carbohydrates that is compatible with the CHARMM force fields for proteins, lipids and nucleic acids, thereby allowing for computational studies of carbohydrates in heterogeneous systems including glycoproteins and glycolipids. The optimized force field parameters will be validated via molecular dynamics (MD) simulation studies of biologically interesting carbohydrate-containing systems for which experimental data are available. Upon completion of the proposed study a better understanding of the structural properties of carbohydrates, ranging for monosaccharides, polysaccharides and carbohydrates in heterogeneous systems, including vaccines and bacterial toxins, will be obtained. In addition, a new empirical force field for carbohydrates will be made available to the scientific community. The availability of a carbohydrate force field that is compatible with available force fields for proteins, lipids and nucleic acids will greatly enhance the applicability of computational approaches to these biologically essential molecules, facilitating the rational design of therapeutic agents, vaccines and counterterrorism agents.