Metadynamics modelling of the solvent effect on primary hydroxyl rotamer equilibria in hexopyranosides.

Accurate modelling of rotamer equilibria for the primary hydroxyl groups of monosaccharides continues to be a great challenge of computational glycochemistry. The metadynamics technique was applied to study the conformational free energy surfaces of methyl alpha-D-glucopyranoside and methyl alpha-D-galactopyranoside, employing the GLYCAM06 force field. For both molecules, seven to eight conformational free-energy minima, differing in the omega (O-5-C-5-C-6-O-6) and chi (C-3-C-4-O-4-HO-4) dihedral angles, were identified in vacuum or in a water environment. The calculated rotamer equilibrium of the primary hydroxyl group is significantly different in vacuum than in water. The major effect of a water environment is the destabilisation of a hydrogen bond between O-4-HO-4 and O-6-HO-6 groups. It was possible to calculate the free-energy differences of individual rotamers with an accuracy of better than 2 kJ/mol. The calculated gg, gt and tg rotamer populations in water are in close agreement with experimental measurements, and therefore support the theoretical background of metadynamics.