Exploring the Origins of Enthalpy-Entropy Compensation by Calorimetric Studies of Cyclodextrin Complexes.

Cyclodextrin complexes were used as simple model systems to explore the enthalpy-entropy compensation phenomenon, which is often observed in biomolecular processes, e.g., in protein-ligand binding. The complexation thermodynamics for the binding of a series of adamantane derivatives to several cyclodextrin hosts were determined by isothermal titration calorimetry in the temperature range 10-55 °C. As for other cyclodextrin complexes, the thermodynamic parameters depended systematically on the structural modifications of the cyclodextrins. Hydroxypropyl chains at the rims of the cyclodextrin hosts changed the thermodynamic fingerprint of binding to all guests by inducing significant increases in the complexation enthalpies and entropies. Similarly, the heat capacity changes upon complexation also showed a linear dependence on the number of hydroxypropyl chains. The altered complexation thermodynamics was ascribed to the increased dehydration of polar groups on the guest by the hydroxypropyl chains on the host. This unfavorable interaction destabilized the complexes as the enthalpic penalty was only partially compensated by the gain in entropy. The degree of enthalpy-entropy compensation depended on the guest molecule and seems to be related to the hydrophilicity/hydrophobicity of the desolvated molecular surface.