Conformational Properties of Glycosaminoglycan Disaccharides: A Molecular Dynamics Study

The structure and conformation of glycosaminoglycans (GAGs) are of central importance to understand the mechanisms behind their functions in biological systems. Due to the inherent chemical and structural heterogeneity of GAGs, focusing on longer, naturally existing GAG chains hinders drawing conclusions on the influence of the chemical functionalization on the basic conformational degree of freedom, that is, the dynamic shape of glycosidic linkage present in the particular disaccharide repeating unit. In the present study, we have considered the complete set of 106 GAG-related disaccharides, being potential building blocks for longer GAG chains (including hyaluronan, chondroitin, keratan, dermatan, and heparan). Both the unfunctionalized units and all possible combinations of either partially or fully sulfated derivatives contribute to this number. The unbiased and enhanced sampling molecular dynamics simulations provide a link to understand the influence of sulfation on the conformational properties of GAG glycosidic linkages. Residue–residue hydrogen bonding is not significant for either the glycosidic linkage conformation or its flexibility. It was found that in the majority of cases, the dominating conformation of the linkage is weakly affected by sulfation and the main role is played by the steric and stereoelectronic effects. However, there exist numerous cases where sulfation increases the contribution of alternative conformations to a nonnegligible extent and, in some rare cases (restricted to disaccharides building heparan), leads to the reorientation of the glycosidic linkage. The identified sulfation sites, being the most important in this context, are C₆ and C₃ at the GlcNAc residue. Finally, the full set of free energy maps relying on the glycosidic dihedral angle values for diverse GAG disaccharides are provided; they may be used for further studies, focused on longer GAG chains.