title: Conformation of sulfated galactan and sulfated fucan in aqueous solutions: implications to their anticoagulant activities.
abstract: 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 alpha-L-galactan and of a alpha-L-fucan with similar structure. Through comparison between theoretical and NMR derived coupling constants, we observed that the pyranose rings are predominantly in the (1)C(4) 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 alpha-L-galactan, but not the alpha-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.
authors.affiliation: Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Av Bento Gonçalves 9500, CP 15005, Porto Alegre 91500-970, Brazil.
authors.forename: Camila F
authors.initials: CF
authors.lastname: Becker
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Guimarães
authors.forename: Paulo A S
authors.initials: PA
authors.lastname: Mourão
authors.forename: Hugo
authors.initials: H
authors.lastname: Verli
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D000991:Antithrombins / Q000737:chemistry; D002236:Carbohydrate Conformation; D003198:Computer Simulation; D005685:Galactans / Q000737:chemistry* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D006868:Hydrolysis; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011134:Polysaccharides / Q000737:chemistry* / Q000494:pharmacology*; D012984:Software; D012996:Solutions; D013816:Thermodynamics; D014867:Water
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D005685:Galactans; D046911:Macromolecular Substances; D011134:Polysaccharides; D012996:Solutions; D014867:Water; C007789:fucoidan