Conformation of sulfated galactan and sulfated fucan in aqueous solutions: Implications to their anticoagulant activities

The discovery of sulfated galactans and sulfated fucans in marine invertebrates with simple and ordered structures opened new perspectives to investigate the biological activity of these molecules and to determine whether different structures confer high affinity for a particular protein. We undertook a conformational analysis of a 2-sulfated, 3-linked α-l-galactan and of a α-l-fucan with similar structure. Through comparison between theoretical and NMR derived coupling constants, we observed that the pyranose rings are predominantly in the 1C4 conformation in these polysaccharides. Additionally, the geometry of the glycosidic linkages was determined based on force field calculations, indicating that the two polysaccharides have similar conformations in solution. Since the sulfated α-l-galactan, but not the α-l-fucan potentiates antithrombin (AT) inhibition of thrombin, the solution conformations of the compounds were docked into AT and the complexes obtained were refined through molecular dynamics calculations. The obtained results indicates extremely different orientations for the two polysaccharides, which well correlates and explain their distinct anticoagulant activities. Finally, the molecular mechanism of a selective 2-desulfation reaction, observed among sulfated fucans, was explained as a consequence of an intramolecular hydrogen bond capable of assisting in the removal of the charged group.