Deciphering the Specific High-Affinity Binding of Cucurbit[7]uril to Amino Acids in Water

• Published in: The journal of physical chemistry. B Vol. 119; no. 13; pp. 4628 - 4636
• Main Authors: Lee, Jong Wha, Lee, Hyun Hee L, Ko, Young Ho, Kim, Kimoon, Kim, Hugh I
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02-04-2015
• Subjects: Affinity; Amino acids; Amino Acids - chemistry; Binding; Bridged-Ring Compounds - chemistry; Calorimetry; Complex formation; Gases - chemistry; Holes; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Imidazoles - chemistry; Ionic mobility; Ions - chemistry; Mass Spectrometry; Molecular Dynamics Simulation; Solutions; Solvation; Solvents - chemistry; Thermodynamics; Water - chemistry
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/acs.jpcb.5b00743

This work presents a systematic study on the host–guest interactions between the macrocyclic host molecule cucurbit[7]­uril (CB[7]) and amino acids (AAs) including three basic AAs (Lys, Arg, and His) and three aromatic AAs (Phe, Tyr, and Trp) to elucidate the origin of the high selectivity of CB[7] toward AA residues in proteins. Complex formation between CB[7] and each AA was examined in solution (by isothermal titration calorimetry and NMR) as well as in the gas phase (by ion mobility mass spectrometry and collision-induced dissociation), and the results were further combined with computational investigations. Generally, the aromatic AAs show higher binding affinities than the basic AAs in buffer solutions with various pH values. On the contrary, the gas-phase stabilities of the basic AA complex ions are higher than those of the aromatic AA complex ions, suggesting that the direct ion–dipole interactions between the charged side chains of the basic AAs and the polar carbonyl groups of CB[7] predominate in the absence of water. The ion–dipole interactions are less significant in water, since the original interactions of the guests with water are lost upon complex formation. In contrast, the transfer of the hydrophobic groups from the bulk into the hydrophobic CB[7] cavity suffers less from the desolvation penalty, resulting in higher binding affinities in water. Therefore, initial guest solvation is another key factor which should be considered when designing high-affinity host–guest systems, in addition to the contribution from the release of high-energy water molecules from the CB[7] cavity (J. Am. Chem. Soc. 2012, 134, 15318–15323).