Separating Enthalpic, Configurational, and Solvation Entropic Components in Host-Guest Binding: Application to Cucurbit[7]uril Complexes through a Full In Silico Approach via Water Nanodroplets

Cucurbiturils are a family of supramolecular hosts obtained by condensation of glycoluril and formaldehyde. Cucurbit[7]uril, CB[7], is the most prominent member of the family for its biomolecular interest, arising from its mild solubility in water and for its strong binding with a large variety of guests containing nonpolar fragments such as adamantanes and ferrocene. For instance, CB[7] encapsulates diamantane diammonium iodide with an attomolar dissociation constant, a value unmatched even in natural encapsulation processes. Computational chemistry has been extensively employed to describe the enthalpic-entropic compensation principle of the molecular recognition process of cucurbituril hosts, but the synergistic contribution of experimental data is required for accurate results to be obtained. This paper proposes the first fully theoretical model able to reconcile the calculated thermodynamics of the complexation process with the experimental data obtained by calorimetry (ITC) for cucurbit[7]uril. The model allows the isolation and estimation of all of the enthalpic and entropic contributions coming from solute and solvent alike to the whole host-guest binding event and enables the straightforward calculation of the contribution of the solvation entropy to the binding.