Theoretical study of structures and charge distributions of 2-, 3- and 6-hydroxypropyl-β-cyclodextrin with different degrees of substitution

Hydroxypropyl-β-cyclodextrin (HPβCD) is a derivative of cyclodextrin extensively used in the pharmaceutical industry, since it improves the solubility of drugs, and widens their oral bioavailability and safety profile. Theoretical studies about HPβCD configurations are important so as to simulate by molecular mechanics and dynamics, the complex formation and enantiomeric separations of these cyclodextrins with other molecules. Twelve structures and charge distributions of 2-, 3- and 6-hydroxypropyl-β-cyclodextrin (2-, 3-, 6-HPβCD) with different degrees of substitution were obtained using ab initio methods. The atomic positions of glucose units, dihedral angles of hydroxypropyl groups (HPs), radius of gyration, and H-bonds formed were analysed in the structures. The 3-HPβCD configurations showed the greatest variations in their atomic positions, their HPs groups being slightly rotated towards the interior of the rim of cyclodextrin and hence narrowing its opening. The structures of 2-HPβCD are the least influenced by the degree of substitution and include fewer H-bonds. Different values for the partial atomic charges for each glucose unit in a molecule were obtained, as well as for all HPβCD configurations. This result, consequence of the ab initio methods used, is a new contribution that can be important to simulate processes in which small energy differences decisively influence the results. The electric potential due to the charge distribution of HPβCDs was calculated inside and outside the cavity. It was found that the changes at each position were mainly due to atomic configurations, since the differences in partial atomic charges are one or two orders of magnitude smaller than in atomic positions.Communicated by Ramaswamy H. Sarma.