pH- and microhydration-corrected DFT insights into cucurbit[7]uril host-guest thermodynamics: toward predictive...

Cucurbit[7]uril (CB[7]) host-guest systems display extraordinary binding affinities, yet predicting their thermodynamic profiles from first principles remains an open challenge. Standard implicit-solvent DFT methods systematically overestimate free energies of inclusion because they neglect structured portal hydration, protonation equilibria, and conformational averaging. Here, we present a hydration- and pH-aware DFT workflow that integrates portal microhydration, charge-state correction, and simple conformer averaging within a unified supramolecular thermodynamic framework. Benchmarking on a small set of canonical CB[7] guests spanning six orders of magnitude in affinity shows that the corrected model substantially reduces the discrepancy with experimental ITC data for these systems and provides chemically transparent insight into how electrostatic and hydrophobic driving forces partition across different classes of cationic guests.

All geometries were optimized using the ωB97X-D/def2-TZVP level of theory with SMD implicit solvation, augmented by 2-4 explicit water molecules at each CB[7] carbonyl portal to account for microhydration and rim desolvation effects. Guest protonation states were corrected using experimental pKₐ values within thermodynamic cycles, and multiple bound conformers were combined through Boltzmann weighting to recover ensemble-averaged free energies. Noncovalent interactions were analyzed via RDG/NCI isosurfaces, revealing dispersion-dominated stabilization in hydrophobic guests and electrostatic enhancement in charged ones. The resulting microhydration- and pH-corrected protocol substantially narrows the discrepancy between simple implicit-solvent DFT and experimental binding free energies for a small benchmark set of CB[7] complexes and provides a mechanistically transparent framework that can be extended and rigorously tested on broader host-guest libraries in future work.