The Anomeric Equilibrium in d -Xylose: Free Energy and the Role of Solvent Structuring

Standard molecular dynamics (MD) and free energy simulations have been used to analyze the anomeric equilibrium for d -xylose in aqueous solution. This molecule was selected as a simple model for the anomeric effect in sugars since there are no complications arising from the rotameric distribution of a primary alcohol. As in previous studies of glucose, the free energy calculations found a small free energy difference (0.15 kcal/mol favoring the α form) between the anomers; the experimental value is also small (−0.38 kcal/mol) but favors the β form. Thermodynamic integration analysis of the components contributing to this result showed that, as in the case of glucose, the free energy difference results from the balance between an internal term favoring the α anomer and a solvation term favoring the β anomer. The validity of the partitioning is confirmed by direct evaluation of the energy difference and its components from long standard MD simulations of each anomer. Hydrogen bonding analysis of the MD simulations provides a mechanistic explanation of the solvation preference for the β anomer. It results from improved hydrogen bonding of the anomeric hydroxyl group in the β anomer as the result of an increased accessible surface area. Three-dimensional averaging demonstrates the anisotropy in the solvent structure surrounding the two solutes and its dependence upon configuration.