Does Inter-Residue Hydrogen Bonding in β-(1→4)-Linked Disaccharides Influence Linkage Conformation in Aqueous Solution?

Two disaccharides, methyl beta-d-galactopyranosyl-(1 -> 4)-alpha-d-glucopyranoside (1) and methyl beta-d-galactopyranosyl-(1 -> 4)-3-deoxy-alpha-d-ribo-hexopyranoside (3), were prepared with selective C-13-enrichment to allow measurement of six trans-O-glycosidic J-couplings ((2)J(COC), (3)J(COCH), and (3)J(COCC)) in each compound. Density functional theory (DFT) was used to parameterize Karplus-like equations that relate these J-couplings to either phi or psi. MA'AT analysis was applied to both linkages to determine mean values of phi and psi in each disaccharide and their associated circular standard deviations (CSDs). Results show that deoxygenation at C3 of 1 has little effect on both the mean values and librational motions of the linkage torsion angles. This finding implies that, if inter-residue hydrogen bonding between O3H and O5 ' of 1 is present in aqueous solution and persistent, it plays little if any role in dictating preferred linkage conformation. Hydrogen bonding may lower the energy of the preferred linkage geometry but does not determine it to any appreciable extent. Aqueous 1-mu s MD simulation supports this conclusion and also indicates greater conformational flexibility in deoxydisaccharide 3 in terms of sampling several, conformationally distinct, higher-energy conformers in solution. The populations of these latter conformers are low (3-14%) and could not be validated by MA'AT analysis. If the MD model is correct, however, C3 deoxygenation does enable conformational sampling over a wider range of phi/psi values, but linkage conformation in the predominant conformer is essentially identical in both 1 and 3.