Complexation Kinetics of Cyclodextrins with Bile Salt Anions: Energy Barriers for the Threading of Ionic Groups

Binding constants for thousands of cyclodextrin complexes have been reported in the literature, but much less is known about the kinetics of these host–guest complexes. In the present study, inclusion complexes of bile salts with β-cyclodextrin, γ-cyclodextrin, and a methylated β-cyclodextrin were studied by nuclear magnetic resonance (NMR) lineshape analysis to explore the structural factors that govern the complexation kinetics. For complexes with β-cyclodextrin, the association rate constants ranged from 2 × 106 to 2 × 107 M–1 s–1 while the dissociation rate constants ranged from 12 to 6000 s–1 at 25 °C. The kinetics were thus significantly slower than for any other β-cyclodextrin complex reported in the literature, due to the large energy barrier for threading the ionic sidechains of the bile salt anions. Bile salts with taurine and glycine sidechains had identical binding affinities, but the kinetics differed by a factor of 10. Introduction of a single hydroxyl group at the binding site of the bile salts reduced the lifetimes and binding constants of the complexes by more than 50 times. The strong temperature dependence of the rate constants revealed that the large activation energies were mainly enthalpic with a small contribution from entropy. The larger γ-cyclodextrin was threaded by the nonionic end of the bile salts, and the kinetics were too fast to be accurately determined. The study demonstrates that ionic groups on guest molecules constitute significant energy barriers for the threading and dethreading of β-cyclodextrin hosts.