Carbohydrate conformation in aqueous solution: Calculation of a QM/MM potential of mean force

The aqueous solution conformation of model disaccharide, 4-O-α-D-xylopyranosyl-α-D-xylopyranose, was investigated using a combined quantum mechanical (QM)/molecular mechanical (MM) potential. In vacuo and aqueous solution conformational free energy surfaces were constructed from potential of mean force calculations, using weighted histogram analysis of 8.5 and 13.5 ns combined QM/MM molecular dynamics simulations, respectively. Calculations suggest a proportion of direct (5%) and water-bridged (34%) intersaccharide hydrogen bonds in aqueous solution, the latter consistent with a broad range of φψ space. Mulliken analysis indicates non-uniform polarisation of carbohydrate electron density, contrasting with electrostatic descriptions employed in force fields based on uniform over-polarisation at the HF/6-31G* level of theory. © 2004 Elsevier B.V. All rights reserved.