Factors controlling relative stability of anomers and hydroxymethyl conformers of glucopyranose

The relative energies of 11 different conformers of D-glucose, including different exo-anomeric orientations and at least one of each hydroxymethyl conformer (G−, G+, and T) for each of the two anomeric forms (α and β), were calculated at much more complete levels of quantum mechanical (QM) electronic structure theory than previously available, and relative free energies in solution were calculated by adding rotational, vibrational, and aqueous solvation effects. The gas-phase results are based on very large basis sets (up to 624 contracted basis functions) and the coupled cluster method for electron correlation. Solvation Model 5.4/ AM1 was used to calculate the effects of aqueous solvation. Factors contributing to the relative energies of these conformers have been analyzed. Relative energies varied considerably (up to 4.5 kcal/mol), depending on the theoretical level, and different levels of theory disagreed as to which anomer was lower in energy. The highest-level gas-phase calculations predicted the α-anomer to be lower in free energy by 0.4 kcal/mol (Boltzmann average). Gas-phase energies from several different classical force fields were compared to QM results. The QM structures optimized at the MP2/cc-pVDZ level of theory compared well with experiment for three different crystal structures. In water, the β-anomers were better solvated than the α-anomers by 0.6 kcal/mol (Boltzmann average). Contributions of individual hydrophilic groups to the solvation free energies were analyzed. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1111–1129, 1998