Computational analysis of oligosaccharide conformations – methodological development, applied studies, and design of glycomimetics

Carbohydrates are the most abundant class of biomolecules. Besides their roles as structural elements and energy storage, they are involved in signaling and recognition processes. Their functions and activities depend on their preferred conformations. The software GLYGAL was developed to perform conformational studies of oligosaccharides using a genetic algorithm tailored for carbohydrates. The new method was applied to the highly branched exopolysaccharide of Burkholderia cepacia. The results show that its heptasaccharide repeating units assume a well defined conformation, stabilized by steric interactions between consecutive units. Furthermore, GLYGAL was used to calculate favorable conformations of histo-blood group antigens. The compounds were then fitted in the binding site of the surface protein of the norovirus VA387 strain and their binding affinity was estimated by molecular dynamics and Glide scoring, giving insights into the interaction patterns involved in norovirus infection. Finally, the mimetic properties of thioglycosidic and selenoglycosidic derivatives of the ABH antigens were studied by conformational and dockings studies, indicating potentially bioactive derivatives with increased resistance to hydrolysis. In conclusion, the computational methodologies developed during this study were successfully used, together with existing methods, for the investigation of natural carbohydrates and the rational design of glycomimetics

Conformation of the exopolysaccharide of Burkholderia cepacia predicted with molecular mechanics (MM3) using genetic algorithm search.

We present a computational conformational analysis of the exopolysaccharide of Burkholderia cepacia, which is believed to play a role in colonization and persistence of B. cepacia in the lungs of cystic fibrosis patients. The repeating unit of the exopolysaccharide is a heptasaccharide with three branches, which cause significant steric restraints. Conformational searches using glygal, an in-house developed software using genetic algorithm search methods, were performed on fragments as well as on the complete repeating unit with wrap-over residues. The force field used for the calculations was MM3(96). The search showed four favored conformations for an isolated repeating unit. However, for a sequence of several repeating units, the calculations indicate a single, well-defined linear conformation