Hydration Ensembles in Proton-Linked Amino-Acid Recognition by Cucurbit[7]uril
Year: 2026
Type: article
Abstract: The hydrophobic effect is often considered a major driving force for molecular recognition in water, whether through classical desolvation of nonpolar surfaces or through the release of confined high-energy water from host cavities. However, the interplay between protonation, ion–dipole interactions, and hydration remains poorly understood. Here we show that amino-acid recognition by cucurbit[7]uril (CB7) is best described as a population-weighted ensemble of proton-linked hydration states, rather than as a single water-release process. By combining pH-dependent isothermal titration calorimetry, X-ray crystallography, molecular dynamics simulations, and interaction-energy analysis, we connect the pH-dependent apparent binding affinities with cavity and portal hydration coupled to ammonium–portal ion–dipole stabilization. Aromatic amino acids differ not by adopting fundamentally different binding modes, but by redistributing population among four hydration states defined by the position of water relative to the cavity and ammonium anchor. Phe and Trp represent opposite limits, with Phe favoring cooperative cavity-water contact and Trp dominated by dry-cavity filling, whereas Tyr and DOPA shift the ensemble toward portal-solvated states. These results show that confined water can strengthen, rather than oppose, hydrophobic recognition when integrated into the ion–dipole binding motif and proton linkage. CB7–amino-acid recognition therefore emerges as a coupled process in which hydrophobic inclusion, ammonium anchoring, hydration, and proton linkage act together.
Institution: University of Warsaw
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Funder: Narodowe Centrum Nauki
Award: G4264553029
OpenAlex ID: W7212066161