Pyranose ring conformations in mono- and oligosaccharides: a combined MD and DFT approach

Among the descriptors of the molecular structure of carbohydrates, the conformation of the pyranose ring is usually the most problematic one to tackle. We present the results of a systematic study oriented at determining the ring-inversion properties of all d-hexopyranoses in the form of monosaccharides, O₁-methylated monosaccharides and homotrisaccharides. Contrary to the existing studies, based either on molecular mechanics force fields or on conformational search within ab initio potentials, we combine the structural information from molecular dynamics simulations performed within the GROMOS 56a6_{CARBO_R} force field and use it in a subsequent geometry optimization procedure, performed at the DFT level of theory. This two-step procedure allows avoiding errors resulting from overestimating the contribution of the hydrogen bond-rich, low-energy structures that are not abundant in aqueous solutions. The calculated anomeric ratios and the populations of staggered conformers of the hydroxymethyl group are in satisfactory agreement with the experimental data. Regarding the ring-inversion properties, for the first time, we achieved good agreement of the ab initio-derived data for all hexopyranoses with the experimentally inferred Angyal scheme and with the NMR-inferred populations of ring conformers. The same computational methodology allows determination of the influence of functionalization (methylation or glycosylation) on the ring-inversion properties which includes the influence of the anomeric effect, enhanced upon O₁-functionalization. In general, the correlation between ring-inversion properties of unfunctionalized monomers and those of O₁-methylated, O₁-glycosylated, O₄-glycosylated and O₁,O₄-diglycosylated monomers is qualitatively (but not quantitatively) compatible with that predicted by the classical force fields.