Conformational properties of glucose-based disaccharides investigated using molecular dynamics simulations with local elevation umbrella sampling

Explicit-solvent molecular dynamics (MD) simulations of the 11 glucose-based disaccharides in water at 300 K and 1 bar are reported. The simulations were carried out with the GROMOS 45A4 force-field and the sampling along the glycosidic dihedral angles phi and psi was artificially enhanced using the local elevation umbrella sampling (LEUS) method. The trajectories are analyzed in terms of free-energy maps, stable and metastable conformational states (relative free energies and estimated transition timescales), intramolecular H-bonds, single molecule configurational entropies, and agreement with experimental data. All disaccharides considered are found to be characterized either by a single stable (overwhelmingly populated) state ((1 -> n)-linked disaccharides with n = 1, 2, 3, or 4) or by two stable (comparably populated and differing in the third glycosidic dihedral angle (omega) over bar; gg or gt) states with a low interconversion barrier ((1 -> 6)-linked disaccharides). Metastable (anti-phi, or anti-psi) states are also identified with relative free energies in the range of 8-22 kJ mol(-1). The 11 compounds can be classified into four families: (i) the alpha(1 -> 1)alpha-linked disaccharide trehalose (axial-axial linkage) presents no metastable state, the lowest configurational entropy, and 110 intramolecular H-bonds; (ii) the four alpha(1 -> n)-linked disaccharides (n = 1, 2, 3, or 4; axial-equatorial linkage) present one metastable (anti-psi) state, an intermediate configurational entropy, and two alternative intramolecular H-bonds; (iii) the four beta(1 -> n)-linked disaccharides (n = 1, 2, 3, or 4; equatorial-equatorial linkage) present two metastable (anti-phi and anti-psi) states, an intermediate configurational entropy, and one intramolecular H-bond; (iv) the two (1 -> 6)-linked disaccharides (additional glycosidic dihedral angle) present no (isomaltose) or a pair of (gentiobiose) metastable (anti-phi) states, the highest configurational entropy, and no intramolecular H-bonds. The observed conformational preferences appear to be dictated by four main driving forces (ring conformational preferences, exo-anomeric effect, steric constraints, and possible presence of a third glycosidic dihedral angle), leaving a secondary role to intramolecular H-bonding and specific solvation effects. In spite of the weak conformational driving force attributed to solvent-exposed H-bonds in water (highly polar protic solvent), intramolecular H-bonds may still have a significant influence on the physico-chemical properties of the disaccharide by decreasing its hydrophilicity. Along with previous work, the results also complete the suggestion of a spectrum of approximate transition timescales for carbohydrates up to the disaccharide level, namely: similar to 30 ps (hydroxyl groups), similar to 1 ns (free lactol group, free hydroxymethyl groups, glycosidic dihedral angle (omega) over bar in (1 -> 6)-linked disaccharides), similar to 10 ns to 2 mu s (ring conformation, glycosidic dihedral angles phi and psi). The calculated average values of the glycosidic torsional angles agree well with the available experimental data, providing validation for the force-field and simulation methodology employed. (C) 2010 Elsevier Ltd. All rights reserved.