The systematic influence of solvent on the conformational features of furanosides.

The endo- and exo-anomeric effects are the two most recognizable stereoelectronic effects exhibited by carbohydrates. Their presence relies on the interactions between ring substituent(s) and ring oxygen atoms. Here, we report the finding of a new effect that partially controls the conformational properties of furanose rings and can be ascribed to the influence of the solvent on the electronic structure of a molecule. In contrast to anomeric effects, it is not dependent on either presence or absence of ring substituents. Its origins lie in a solvent-induced flux of atomic charges that involves atoms forming the furanose ring. This systematically changes the energy of the whole molecular system and alters the ring-distortion free energies by ∼2.5-6.5 kJ mol-1, favoring the geometries close to the twist 3T2/2T3 conformers and disfavoring the envelope OE/EO-like shapes. This intriguing effect has never been reported before, although it is expected to exist in all furanose rings. Along with more recognized stereoelectronic effects, this phenomenon contributes to a wide applicability of the two-state (north vs. south) model of pseudorotation in furanosides and, in the case of extremely flexible furanose rings, may change the preferred conformation type in comparison with the gas-phase-oriented predictions.

A GROMOS Force Field for Furanose-Based Carbohydrates.

The article describes a GROMOS force field parameter set for molecular dynamics simulations of furanose carbohydrates. The proposed united-atom force field is designed and validated with respect to the conformational properties of furanose mono-, di-, oligo-, and polymers in aqueous solvent. The set accounts for the possibility of arbitrary glycosidic linkage connectivity between units, O-alkylation, as well as of different anomery. The compatibility with the already existing, pyranose-dedicated GROMOS 56A6CARBO/CARBO_R set allows one to use the presently proposed extension for studying more diverse and biologically relevant carbohydrates that exploit both pyranose and furanose units. The validation performed against the quantum-mechanical and experimental data concerning the structural and conformational features shows that the newly developed set is capable to reproduce conformational equilibrium within the furanose ring, relative free energies of anomers, hydroxymethyl rotamers, and glycosidic linkage conformers. Additionally, the results concerning the conformation of the furanose ring with relation to the two-state model as well as other conformational features of furanose-containing saccharides are discussed.

Tautomeric and epimeric equilibria of aldo- and ketohexoses studied by the MD simulations and QM calculations.

The article is devoted to the problem of molecular modeling of tautomeric and epimeric equilibria in aqueous solutions of unfunctionalized d-aldo- and d-ketohexoses. We have applied the computational protocol proposed in our previous article [Gaweda, Plazinski, Phys. Chem. Chem. Phys., 2017, 19, 20760-20772, doi:10.1039/c7cp02920a], originally designed to study the conformational features of saccharides, in order to check whether it can be extended to the case of tautomeric/epimeric equilibria of monosaccharides. The results show that the most important trends are correctly reflected in a qualitative manner, i.e. within the limits of 'chemical accuracy' (∼±4 kJ/mol). Insight into the calculated conformational energies provides a molecular interpretation of the tautomeric preferences of aldohexoses, according to which the pyranose/furanose ratio is determined mainly by the energy level of pyranose forms, whereas the energies of furanose forms are approximately constant along the series. The investigated paths of epimerization suggest that epimerization of aldohexopyranoses at any center favors the equatorial arrangements of the hydroxyl group. The energetic effects of epimerization in furanoses are significantly lower and do not exhibit related systematic trends.

Extension of the GROMOS 56a6CARBO/CARBO_R Force Field for Charged, Protonated, and Esterified Uronates.

An extension of the GROMOS 56a6CARBO/CARBO_R force field for hexopyranose-based carbohydrates is presented. The additional parameters describe the conformational properties of uronate residues. The three distinct chemical states of the carboxyl group are considered: deprotonated (negatively charged), protonated (neutral), and esterified (neutral). The parametrization procedure was based on quantum-chemical calculations, and the resulting parameters were tested in the context of (i) flexibility of the pyranose rings under different pH conditions, (ii) conformation of the glycosidic linkage of the (1 → 4)-type for uronates with different chemical states of carboxyl moieties, (iii) conformation of the exocyclic (i.e., carboxylate and lactol) moieties, and (iv) structure of the Ca2+-linked chain-chain complexes of uronates. The presently proposed parameters in combination with the 56a6CARBO/CARBO_R set can be used to describe the naturally occurring polyuronates, composed either of homogeneous (e.g., glucuronans) or heterogeneous (e.g., pectins, alginates) segments. The results of simulations relying on the new set of parameters indicate that the conformation of glycosidic linkage is nearly unaffected by the chemical state of the carboxyl group, in contrary to the ring conformational equilibria. The calculations for the poly(α-d-galacturonate)-Ca2+ and poly(α-l-guluronate)-Ca2+ complexes show that both parallel and anitiparallel arrangements of uronate chains are possible but differ in several structural aspects.

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 56a6CARBO_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.