Conformational analysis of diglycosyl disulphides containing ßS(1-1)S interglycosidic linkages

Abstract

Includes bibliographical references.The conformation around the glycosidic linkage has been shown to be the single most important factor in determining the molecular shape of oligosaccharides. This property is of fundamental importance in influencing biological activity such as binding to enzymes or receptors. Therefore, knowledge of the conformational preference associated with glycosidic linkages is required. In this thesis the conformational preferences of the βS( 1-.1 ')8 glycosidic linkage within asymmetrical dissacharide mimetics have been studied using computational methods. The sulphur-sulphur torsion angle parameters contained in the CHARMM22 force field were refined based on density functional theory (OFT) calculations of dimethyl disulphide, which is a representative fragment containing the sulphur-sulphur torsion angle. The refined parameters were then used in molecular dynamics (MD) simulations of three disaccharide mimetics in vacuum, water and dimethyl sulphoxide (OM80). The resulting conformational analysis reveals that in the case of disaccharides containing unsubstituted glycosyl rings, good agreement with experimental nuclear overhauser effects (NOEs) and spin-spin coupling constants is obtained. However, for disaccharides containing substituted glycosyl rings poorer agreement with experimental data is obtained, which may suggest that further refinement of the force field is required. In addition, a natural bond orbital analysis was conducted on the 1, I' - disulphanediyl diethanol fragment to investigate the origin of the conformational preference for the +g and -g conformers of the sulphur-sulphur torsion angle. This phenomenon is shown to be as a result of a two-electron stabilising [no – σ*c-s] delocalisation from the lone pair of the oxygen atoms to the carbon-sulphur antibonding orbitals