Supramolecular gating of guest release from cucurbit[7]uril using de novo design

Herein we computationally explore the modulation of the release kinetics of an encapsulated guest molecule from the cucurbit[7]uril (CB7) cavity by ligands binding to the host portal. We uncovered a correlation between the ligand-binding affinity with CB7 and the guest residence time, allowing us to rapidly predict the release kinetics through straightforward energy minimization calculations. These high-throughput predictions in turn enable a Monte-Carlo Tree Search (MCTS) to de novo design a series of cap-shaped ligand molecules with large binding affinities and boosting guest residence times by up to 7 orders of magnitude. Notably, halogenated aromatic compounds emerge as top-ranking ligands. Detailed modeling suggests the presence of halogen-bonding between the ligands and the CB7 portal. Meanwhile, the binding of top-ranked ligands is supported by H-1 NMR and 2D DOSY-NMR. Our findings open up possibilities in gating of molecular transport through a nanoscale cavity with potential applications in nanopore technology and controlled drug release.

Automated summary

This study computationally explores the modulation of the release kinetics of a guest molecule from the CB7 cavity by ligands binding to the host portal. A correlation between ligand-binding affinity with CB7 and guest residence time is uncovered, allowing for rapid prediction of release kinetics. The study also designs cap-shaped ligand molecules with large binding affinities to significantly boost guest residence times. Notably, halogenated aromatic compounds emerge as top-ranking ligands, and their binding to CB7 is supported by experimental evidence.