Intramolecular hydrogen-bonding in aqueous carbohydrates as a cause or consequence of conformational preferences: a molecular dynamics study of cellobiose stereoisomers

It is often assumed that intramolecular hydrogen-bonding (H-bonding) exerts a significant influence on the conformational properties of aqueous (bio-)polymers. To discuss this statement, one should, however, distinguish between solvent-exposed and buried H-bonds, and between their respective roles in promoting stability (i.e., as a driving force) and specificity (for which the term steering force is introduced here). In this study, the role of solvent-exposed H-bonding in carbohydrates as a driving or steering force is probed using explicit-solvent molecular dynamics simulations with local elevation umbrella sampling in the simple context of cellobiose stereoisomers. More specifically, four β(1→4)-linked d-aldohexopyranose disaccharides are considered, which present a different stereochemisty of the potentially H-bonding groups neighboring the glycosidic linkage. Although the epimerization may largely alter the intramolecular trans-glycosidic H-bonding pattern, it is found to have only very limited influence on the Ramachandran free-energy map of the disaccharide, a loss of intramolecular H-bonding being merely compensated for by an enhancement of the interaction with the solvent molecules. This finding suggests that solvent-exposed trans-glycosidic H-bonding (and in particular the $$\hbox{HO}_3^{\prime}$$ →O5 H-bond) is not the cause of the 21-helical secondary structure characteristic of cellooligosaccharides, but rather the opportunistic consequence of a sterically and stereoelectronically dictated conformational preference. In other words, for these compounds, solvent-exposed H-bonding appears to represent a minor (possibly adverse) conformational driving as well as steering forc