Grant: Discovery Grants Program - Individual

To create innovative treatments and diagnostic tools for disease, novel biochemical pathways need to be targeted. Gaining an understanding of how a biochemical process occurs can aid in the development of therapeutics to treat disease and new tools for diagnostics. One biochemical pathway that is of interest for the treatment of cancer, bacterial infections and viral infections is the synthesis of carbohydrate chains. These carbohydrates chains (glycans) play an important role in cell-cell communication, and the composition of the glycan dictates the information that is stored and relayed between the cells. Biochemical systems achieve highly specific recognition of carbohydrates, with slight changes to the carbohydrate structure dictating whether the carbohydrate contributes to the normal function of an organism or leads to a deleterious effect. Glycans are made within cells through a group of enzymes known as glycosyltransferases and understanding the function of these enzymes is an important step in controlling the information communicated between cells and preventing disease. Nevertheless, many questions remain about how these enzymes function. Specifically, it is unknown how glycosyltransferases specifically bind their carbohydrate substrates, when carbohydrates have little variation in structure. Furthermore, glycosyltransferases are embedded within the cell membrane but the role the membrane plays in the mechanism of action has yet to be determined. Finally, many questions remain about features of the reaction mechanism catalysed by glycosyltransferases. My long-term goal is to gain a fundamental understanding of the structure and function of glycosyltransferases and the factors that give rise to specific binding of carbohydrates. My research program uses computational chemistry to understand these systems. By using a variety of computational techniques that look at the structural and energetic features of the systems (e.g., density functional theory, atomistic molecular dynamics simulations, hybrid QM/MM reaction mechanism calculations and coarse-grained molecular dynamics simulations) different features can be elucidated at high spatiotemporal resolution. The fundamental insight gained on the synthesis and binding of glycans through my research program can be used to direct future development of novel pharmaceuticals for diseases such as cancer, bacterial infections, or viral infections.