Can the anomalous aqueous solubility of β-cyclodextrin be explained by its hydration free energy alone?

Abstract

The well-documented anomalous solubility of β-cyclodextrin (β-CD), relative to α- and γ-CD, has been examined by Naidoo et al. (J. Phys. Chem. B, 2004, 108, 4236–4238.) from the perspective of water organization and internal motion of the macrocyclic rings. Whether modulation in the hydration patterns and in the rigidity of the molecular scaffold can be reconciled with the hydration free energy of β-CD to rationalize its notorious low solubility remains open to further investigation. In this contribution, multi-nanosecond molecular dynamics (MD) simulations have been carried out to investigate the hydration process of α-, β- and γ-CD. The distribution of water molecules involved in this process and the linearity of intramolecular hydrogen bonds have been analyzed. The results reported here demonstrate that the anomalous solubility for β-CD can be essentially rationalized by its greater rigidity conferred by the participating intramolecular hydrogen bonds and the higher density of water molecules of lesser mobility. The hydration free energy of α-, β- and γ-CD was computed using the free energy perturbation method. This quantity is shown to increase with the number of glucose units, thereby suggesting that the anomalous solubility of β-CD cannot be explained by its free energy of hydration alone.