Chelate effect in cyclodextrin dimers: A computational (MD, MM/PBSA, and MM/GBSA) study

The complexation of an adamantyl-phosphate derivative with one β-cyclodextrin, with two β-cyclodextrins, and with two β-cyclodextrins dimerized with a disulfide bridge was studied by computational methods (MD, MM/PBSA, and MM/GBSA) to analyze and rationalize the chelate effect. Although this effect is usually explained by invoking favorable entropy contribution due to the preorganization of the ligand, it has been determined experimentally that in this case it is enthalpy-driven. The computational results are in accord with this finding, although the entropy contribution due to the solvent structural organization around the complex is crucial for the final estimates of the free energy of complexation. © 2006 American Chemical Society.