Solvent‐Modulated Influence of Intramolecular Hydrogen‐Bonding on the Conformational Properties of the Hydroxymethyl Group in Glucose and Galactose: A Molecular Dynamics Simulation Study

Abstract

Intramolecular hydrogen‐bonding (H‐bonding) is commonly regarded as a major determinant of the conformation of (bio)molecules. However, in an aqueous environment, solvent‐exposed H‐bonds are likely to represent only a marginal (possibly adverse) conformational driving as well as steering force. For example, the hydroxymethyl rotamers of glucose and galactose permitting the formation of an intramolecular H‐bond with the adjacent hydroxyl group are not favored in water but, in the opposite, least populated. This is because the solvent‐exposed H‐bond is dielectrically screened as well as subject to intense H‐bonding competition by the water molecules. In the present study, the effect of a decrease in the solvent polarity on this rotameric equilibrium is probed using molecular dynamics simulation. This is done by considering six physical solvents (H2O, DMSO, MeOH, CHCl3, CCl4, and vacuum), along with 19 artificial water‐like solvent models for which the dielectric permittivity and H‐bonding capacity can be modulated independently via a scaling of the O–H distance and of the atomic partial charges. In the high polarity solvents, the intramolecular H‐bond is observed, but arises as an opportunistic consequence of the proximity of the H‐bonding partners in a given rotameric state. Only when the polarity of the solvent is decreased does the intramolecular H‐bond start to induce a conformational pressure on the rotameric equilibrium. The artificial solvent series also reveals that the effects of the solvent permittivity and of its H‐bonding capacity mutually enhance each other, with a slightly larger influence of the permittivity. The hydroxymethyl conformation in hexopyranoses appears to be particularly sensitive to solvent‐polarity effects because the H‐bond involving the hydroxymethyl group is only one out of up to five H‐bonds capable of forming a network around the ring.

Validation and Comparison of Force Fields for Native Cyclodextrins in Aqueous Solution

“…Unfortunately, due to a lack of experimental data, it is not possible to judge which observed hydrogen bonds are the most realistic ones. However, we note that differences between the GROMOS force fields on the one hand and CHARMM36/q4md-CD on the other may not only be caused by the intramolecular interactions but also by the different water models …”

“…However, we note that differences between the GROMOS force fields on the one hand and CHARMM36/q4md-CD on the other may not only be caused by the intramolecular interactions but also by the different water models. 177 Hydration Pattern. Figure 8 shows cylindrical distribution functions describing the water density around α-cyclodextrin calculated with all investigated force fields.…”

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

“…Interestingly, the favorable orientations of the protonated carboxyl group are those that permit the formation of hydrogen bonding with hydroxyl group at C 4 (which can be either axially or equatorially oriented as reflected by different positions of dominating peaks in Figure 6). Although this effect is not necessarily imposed by the presence of such interactions, 85,86 the behavior opposite to that typical for unfunctionalized hexopyranoses and hydroxymethyl group is worth emphasizing.…”

Reinvestigation of N,N-Diacetylimido-Protected 2-Aminothioglycosides in O-Glycosylation: Intermolecular Hydrogen Bonds Contributing to 1,2-Orthoamide Formation

“…For Gal-3,4-diol ( 2d ), however, the concentration-dependent experiment, as depicted in Figure C, is not quite flat as a regular linear relationship. Galactose forms an intramolecular cis -vicinal 3-O/4O–H-bond in aqueous environments . Bearing protections, Gal-3,4-diol 2d in DMSO- d 6 also forms intramolecular HBs, and HMBC discloses correlations between 3O–H and 5-C and between 4O–H and 2-C (Figure D), which gives rise to two possibilities: either the intramolecular HBs are a mixture of 3-O/4O–H and 4-O/3O–H bonds, or the diol forms the intramolecular HB and intermolecular bonds with other 2d molecules at the same time.…”