Abstract
Density functional theory (DFT) has provided detailed information on the molecular structure and spin–spin coupling constants of heparin tetrasaccharide (GlcNS,6S-IdoA2S-GlcNS,6S-IdoA2S-OMe) representing the predominant heparin repeating-sequence. The fully optimised molecular structures of two tetrasaccharide conformations (differing from each other in the conformational form of the sulphated iduronic acid residue–one 1C4 and the other 2S0) were obtained using the B3LYP/6-311+G(d,p) level of theory and applying explicit water molecules to simulate the presence of a solvent. The theoretical data provided insight into variations of the bond lengths, bond angles and torsion angles, formations of intra- and intermolecular hydrogen bonds and ionic interactions. Optimised molecular structures indicated the formation of a complex hydrogen bond network, including interresidue and intraresidue bonds. The ionic interactions strongly influence the first hydration shell and, together with hydrogen bonds, play an important role in shaping the 3D tetrasaccharide structure. DFT-derived indirect three–bond proton–proton coupling constants (3JH-C-C-H) showed that the best agreement with experiment was obtained with a weighted average of 67:33 (1C4:2S0) of the IdoA2S forms. Detailed analysis of Fermi-contact contributions to 3JH-C-C-H showed that important contributions arise from the oxygen lone pairs of neighbouring oxygen atoms. The analysis also showed that the magnitude of diamagnetic spin–orbit contributions are sufficiently large to determine the magnitude of some proton–proton coupling constants. The data highlight the need to use appropriate quantum-chemical calculations for a detailed understanding of the solution properties of heparin oligosaccharides.
Highlights
The relationship between the molecular structure of carbohydrates and their properties is indispensable for understanding essential processes in glycobiology
The analysis showed that the magnitude of diamagnetic spin–orbit contributions are sufficiently large to determine the magnitude of some proton–proton coupling constants
The computed geometry of both heparin tetrasaccharide forms 1 and 2 indicate that bond lengths, bond angles and torsion angles vary with the conformation of the IdoA2S ring (Tables 1 and 2)
Summary
The relationship between the molecular structure of carbohydrates and their properties is indispensable for understanding essential processes in glycobiology. Glycosaminoglycans, such as heparin, belong to the widely studied carbohydrate molecules, which play vital roles in blood coagulation, cell differentiation, viral infection or inflammation [1,2,3,4]. Its oligosaccharides, are structurally rather complex molecules that are composed of repeating disaccharide units comprising a uronate (either β-D-glucuronate or α-L-iduronate) and a hexosamine, 2-amino-2-deoxy α-D-glucose (α-D-glucosamine). The repeating disaccharide can be substituted by O- and N-sulphate groups biosynthetically, through a series of sulphotransferase enzymes at positions 2-O- of the uronate and 6-O- (or more rarely, position 3-O-) of the glucosamine residue. The glucosamine is predominantly N-sulphated, the remainder bearing N-acetyl groups and, none of the Molecules 2018, 23, 3042; doi:10.3390/molecules23113042 www.mdpi.com/journal/molecules
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