Comparative analysis of ganglioside conformations by MD simulations: implications for specific recognition by proteins

Abstract

The accessible conformations of ganglioside headgroups belonging to the GM-(GM3, GM2, GM1, GM1b), GD-(GD3, GD2, GD1a, GD1b) and GT-(GT1a, GT1b) series have been determined using molecular dynamics (MD) simulations. Three to five 1 ns simulations have been run for each oligosaccharide by considering water molecules explicitly. The conformational space accessed by individual glycosidic linkages is the same in all the gangliosides and is similar to that in corresponding disaccharides. Transitions between the different minimum energy regions in the disaccharide map were also observed, especially in the gangliosides of GM- and GD-series. Some of the conformers that correspond to high-energy minima in disaccharide maps are accessed for longer durations probably due to the stabilising effect of the remote-residue interactions possible in these conformations. Comparison of the conformational preferences of specific pairs of gangliosides shows that the addition/deletion of residues (i.e. GM2 vs. GM3, etc.) does not seem to bring about any significant change in the accessible conformations of the rest of the molecule. The α2→3- and the β1→4- branches do not have a significant effect on each other's conformational freedom even though they are on the adjacent hydroxyl groups of galactose. The ganglioside headgroups can thus present a variety of shapes and surfaces to the receptor for binding due to the flexibility associated with glycosidic linkages, especially the branches. The results from the present MD simulations have been able to provide a stereochemical explanation for the observed specificities of some of the ganglioside-binding proteins such as bacterial toxins.