X-ray crystallography and molecular dynamics studies of the inclusion complexes of geraniol in β-cyclodextrin, heptakis (2,6-di-O-methyl)-β-cyclodextrin and heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin

The inclusion of the linear monoterpene, geraniol (gr) in β-cyclodextrin (β-CD), heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD) has been studied by X-ray crystallography and Molecular Dynamics simulations. The gr/β-CD complex crystallizes as a head-to-head dimer in the P21 space group stacking along the crystallographic a-axis in a channel packing mode. Two guest molecules are accommodated almost axially inside the dimeric cavity with their aliphatic ends laying in the interface region of the dimer facing each other and their hydroxylic ends protruding from the narrow β-CD rims. The guest molecules of the adjacent dimers in a channel are interconnected via CH ⋯O and hydrogen bonds forming an internal wire. Both the gr/DM-β-CD and gr/TM-β-CD complexes crystallize in the P212121 space group and stack along the crystallographic b-axis in a head-to-tail manner. DM-β-CD host adopts the conformation of a rigid and well-shaped open cone upon complexation, in which the guest molecule is found highly disordered over 5 sites with varying depths of immersion. The gr/DM-β-CD complex units are arranged in channels and the gr molecules within these channels are also interconnected via CH ⋯O bonds. On the other hand, TM-β-CD host is found severely distorted adopting a ‘closed’ cup-shaped conformation. The guest is partially encapsulated in the wide rim of TM-β-CD and it is found disordered over 3 sites with quite different orientations. The complex units are arranged forming screw channels, with the main part of the guest laying outside the host cavity and filling the intermediate space between the succeeding hosts. The MD analysis based on the crystallographically determined structures sheds light on the dynamic behavior of the geraniol upon complexation with these hosts, its conformation variations and the interconversion of the inclusion modes in solution. Finally, MM/GBSA-calculations revealed that the ascending order in binding affinity ΔG values is: gr/TM-β-CD