Supramolecular gating of guest release from cucurbit[7]uril using de novo design
Hugues Lambert, Alvaro Castillo Bonillo, Qiang Zhu, Yong‐Wei Zhang, Tung‐Chun Lee
Abstract
Abstract 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 1 H 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.