[NMR paper] The Solution Structure of Heparin Pentasaccharide: NMR and DFT Analysis.

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The Solution Structure of Heparin Pentasaccharide: NMR and DFT Analysis.

Related Articles The Solution Structure of Heparin Pentasaccharide: NMR and DFT Analysis.

J Phys Chem B. 2015 Sep 4;

Authors: Hricovini M

Abstract
High-resolution NMR and density functional theory (DFT) calculations have been applied into analysis of heparin pentasaccharide 3D structure in aqueous solution. The fully optimized molecular geometry of two pentasaccharide conformations (differing from each other in the form, one 1C4 and the other 2S0, of the sulfated iduronic acid residue) were obtained using the B3LYP/6-311+G(d,p) level of theory in the presence of solvent, the latter included as explicit water molecules. The presented approach enabled the insight into variations of the bond lengths, bond angles and torsion angles, formations of intra- and intermolecular hydrogen bonds and ionic interactions in the two pentasaccharide conformations. A rather complex hydrogen bond network is formed, including inter-residue and intra-residue bonds between the NH group in the GlcN,3,6S with oxygens linked to C-2 at the IdoA2S residue, and the glycosidic O-1 and the neighboring OSO3- group linked to C-3 in the same residue. On the other hand, as the first hydration shell is strongly influenced by strong ion-ion and ion-dipole interactions between sodium ions, sulfates, carboxylates, and -OH groups, ionic interactions play an important role in the stabilization of the 3D structure. The DFT-computed three-bond proton-proton coupling constants also showed that best agreement with experiment was obtained with a weighted average of 15:85 (1C4:2S0) of the sulfated iduronic acid forms indicating that the ratio is even more shifted towards the 2S0 form than previously supposed. The DFT-computed pentasaccharide conformation differs compared to the previously published data, with the main changes at the glycosidic linkages, namely, the ?1 torsion angles and the ?3 angle. The comparison of the glycosidic linkage torsion angle values in solution with the antithromin-pentasaccharide complex also indicates that the pentasaccharide conformation changes upon binding to antithrombin III. The data supports the assumption that the protein selects the more populated 2S0 conformer of heparin pentasaccharide and, consequently, the binding process of heparin pentasaccharide with antithrombin III is energetically more favorable than formerly expected.


PMID: 26340667 [PubMed - as supplied by publisher]



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