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.