Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

This study reports in detail the results of systematic large-scale theoretical investigations of the acidic dimeric structural units (D-E, E-F, F-G, and G-H) and pentamer D-E-F-G-H (fondaparinux) of the glycosaminoglycan heparin, and their anionic forms. The geometries and energies of these oligomers have been computed using HF/6-31G(d), Becke3LYP/6-31G(d), and Becke3LYP/6-311+G(d,p) methods. The optimized geometries indicate that the most stable structure of these units in the neutral state is stabilized via a system of intramolecular hydrogen bonds. The equilibrium structure of these species changed appreciably upon dissociation. Water has a remarkable effect on the geometry of the anions studied. Because of high negative charge, the solvent effect also resulted in an appreciable energetic stabilization of biologically active anionic forms of these glycosaminoglycans. The stable energy conformations around glycosidic bonds found for dimers and pentamer investigated are compared and discussed with the available experimental X-ray structural data for the structurally related heparin-derived pentasaccharides in cocrystals with proteins.