Separating Enthalpic, Configurational, and Solvation Entropic Components in Host–Guest Binding: Application to Cucurbit[7]uril Complexes through a FullIn SilicoApproach via Water Nanodroplets

Abstract

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.

CB[7]- and CB[8]-Based [2]-(Pseudo)rotaxanes with Triphenylphosphonium-Capped Threads: Serendipitous Discovery of a New High-Affinity Binding Motif

“…In particular, the 1 H spectrum in D 2 O showed an appropriate integration of the asymmetric protons for CB[7] in relation with the axle nuclei, with chemical shifts for H f‑h consistent with the expected shielding caused by the positioning of the central bis-pyridinium moiety within the host (Figure c). This later observation was also found in good agreement with the DFT-optimized geometry obtained for a local minimum of the [2]­rotaxane (Figure a). − DOSY NMR also supported the formation of the MIM, with all of the resonances for the compound diffusing as a whole on the recorded spectrum (see Figure S5).…”

“…Furthermore, the 31 P NMR signal for 1 a 2+ was also downshifted ΔδP a = 0.73 ppm, in good agreement with the discussed insertion mode . Dispersion-corrected calculations carried out for 1 a 2+ ⊂CB­[7] supported this end, − being the local minimum m 1 found for the insertion of the pyridyl group within CB[7], 2.1 kcal/mol more stable than that corresponding to the inclusion of the xylylene moiety ( m 2 , Figure d).…”

“…The red line in the inset shows the fit to a 1:1 binding model. (d) Schematic representation of the two energy minima m 1 and m 2 found for 1 a 2+ ⊂CB­[7] using DFT methods. − …”

“…Schematic representation of the four energy minima m′ 1 -m′ 4 found for complexes 1 a 2+ ⊂CB­[8] using DFT methods. − …”