Conformational analysis of oligosaccharides corresponding to the cell-wall polysaccharide of the Streptococcus group A by Metropolis Monte Carlo simulations

Metropolis Monte Carlo simulations have been performed on four substructures from the cell-wall polysaccharide antigen of Streptococcus group A to explore the conformational behaviour of these compounds. The compounds examined are the trisaccharide, propyl 3-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-2-O-(α-l-rhamnopyranosyl)-α-l-rhamnopyranoside, 1, the tetrasaccharide, propyl 3-O-(3-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-2-O-(α- l-rhamnopyranosyl)-α-l-rhamnopyranosyl)-α-l-rhamnopyranoside, 2, the hexasaccharide, propyl 3-O-(2-O-(3-O-(3-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-α-l-rhamnopyranosyl)-α- l-rhamnopyranosyl)-3-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-α-l-rhamnopyranosyl)-α-l- rhamnopyranoside, 3, and the hexasaccharide, propyl 3-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-2-O-(3-O-(3-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-2-O- (α-l-rhamnopyranosyl)-α-l-rhamnopyranosyl)-α-l-rhamnopyranoside, 4. In general, the conformational flexibility of similar glycosidic linkages in different compounds is comparable. However, in a few cases, small differences in the conformations available to these linkages in different structural environments could be detected. Interestingly, a second conformation found for the β-d-GlcNAc-(1 → 3)-α-l-Rha linkage in three of the compounds was not populated in the hexasaccharide 4. Furthermore, a conformational locale of the α-l-Rha-(1 → 3)-α-l-Rha linkage found to be populated in the trisaccharide 1, tetrasaccharide 2, and hexasaccharide 4 is negligibly populated in the hexasaccharide 3. Ensemble averaged proton-proton distances compare favourably with experimental average distances obtained from NMR spectroscopy. The trisaccharide branch point in the hexasaccharides is shown to be a highly defined conformational feature. The same unit has been found to be one of the crucial elements recognized by anti-Group A Streptococcus antibodies, a result that has implications for the design of improved immunodiagnostics and vaccines.