Cucurbit[n]urils (CBn) bind guest molecules through a combination of electrostatic interactions with the carbonyl rims and hydrophobic interactions with the inner cavity. Investigations with solvatochromic probes in CB7 reveal that the polarity of the cavity resembles that of alcohols (e.g., n‐octanol), while its polarizability (P=0.12) and apparent refractive index (nD=1.10±0.12) are extremely low, close to the gas phase. The calculated molecular quadrupole moments of CBs are extremely large (Θzz=−120 to −340 Buckingham). A survey of reported binding constants of neutral guests and hydrophobic residues that form 1 : 1 inclusion complexes with CB6, reveals a preferential inclusion of C3–C5 residues in its cavity. The largest guests which show non‐negligible binding contain 7 heavy atoms (excluding hydrogen). For CB7, the strongest binding is observed for guests with adamantyl (10 heavy atoms) and ferrocenyl groups (11 heavy atoms), while the largest guests known to be complexed are carborane and the adduct of two pyridine derivatives (12 heavy atoms). The evaluation of different volumes shows that the most meaningful cavity, namely that responsible for binding of hydrophobic residues, is confined by the planes through the oxygen carbonyls. The volume of this inner cavity follows the formula V/Å3=68+62(n−5)+12.5(n−5)2, affording representative cavity volumes of 68 Å3 for CB5, 142 Å3 for CB6, 242 Å3 for CB7, and 367 Å3 for CB8. The volume of the 2 bond dipole regions is comparably smaller, amounting, for example, to 2×35 Å3 for CB6. The analysis of packing coefficients for representative sets of known guests with clearly defined hydrophobic binding motifs reveals average values of 47 % for CB5, 58 % for CB6, 52 % for CB7, and 53 % for CB8, which are well in line with the preferred packing (“55 % solution”, see S. Mecozzi, J. Rebek, Chem. Eur. J. 1998, 4, 1016–1022) in related supramolecular host–guest assemblies. The driving force for binding of hydrophobic guests and residues by CBs is interpreted in terms of the unimportance of dispersion interactions (owing to the low polarizability of their cavity) and the dominance of classical and nonclassical hydrophobic effects related to the removal of very‐high‐energy water molecules (2 for CB5, 4 for CB6, 8 for CB7, and 12 for CB8) from the cavity.

Hydrocarbons are no longer afraid of water when they are reversibly encapsulated by cucurbituril (see picture). The pumpkin‐shaped molecular container displays a high affinity and selectivity towards neutral molecules in salt‐free aqueous solutions. A supramolecular sensing ensemble, composed of cucurbit[6]uril and an anchored indicator dye, is introduced as a highly sensitive fluorescence‐based online detection tool for gas binding in solution.

The host-guest complexation of hydrocarbons (22 guest molecules) with cucurbit[7]uril (CB7) was investigated in aqueous solution. Association constants were determined by using the indicator displacement strategy, which allows binding constant determinations also for poorly water-soluble (hydrophobic) guests. The binding constants (103–109 M−1) increased with the size of the hydrocarbon, pointing to the hydrophobic effect and dispersion interactions as driving forces. Besides potential applications for the sensing and separation of hydrocarbons, the measured affinities provide unique benchmark data for the binding of neutral guest molecules. Consequently, a computational blind challenge, the HYDROPHOBE challenge, was conducted in order to allow a comparison with state-of-the-art computational methods for predicting host-guest affinity constants. In total, 5 computational data sets were submitted, which allowed the comparison of experimental binding constants with those predicted by coupled-cluster theory (DLPNO-CCSD(T)), dispersion-corrected density functional theory (DFT), and explicit solvent molecular dynamics (MD) simulations parameterized with two different force field combinations from the AMBER simulation package. All submissions were capable of predicting the general binding trend, with a slightly better correlation for the MD compared to the quantum-chemical (QM) data sets (R2MD = 0.80 vs R2QM = 0.66, average values for the submitted data sets). On the other hand, QM calculations showed better predictions for the absolute values of the binding affinities as reflected by the mean signed errors (4.3 kcal mol−1 for MD vs 1.8 kcal mol−1 for QM). When searching for sources of uncertainty in predicting the host-guest affinities, the experimentally known hydration energies of the investigated hydrocarbons could be employed, which provided a distinct advantage of the HYDROPHOBE challenge. The comparison with the employed solvation models (explicit solvent for MD and COSMO-RS for QM) confirmed a good correlation for both methods, but revealed a rather constant offset of the COSMO data, by ca. +2 kcal mol−1, which was traced back to a required reference-state correction in the QM submissions (2.38 kcal mol−1). Introduction of the reference-state correction improved the predictive power of the QM methods, particularly for small hydrocarbons up to C5. The correlations of both QM and MD submissions also exposed specific outliers, which could be due to peculiarities of the investigated guests, for example, different degrees of conformational changes upon complexation, such as helical structures of the longer n-alkyl chains within the cavity. The latter was confirmed by 2D NMR experiments and both the MD as well as QM calculations.

The demand for practical and convenient enzyme assays for histone lysine methyltransferases (HKMTs) emerges along with the rapid development of this young class of enzymes. A supramolecular reporter pair composed of p-sulfonatocalix[4]arene (CX4) and the fluorescent dye lucigenin (LCG) has been used to monitor enzymatic trimethylation of lysine residues in peptide substrates. The assay affords a switch-ON fluorescence response and operates in a continuous, real-time, and label-free fashion. The underlying working principle relies on the higher affinity of the macrocycle towards the trimethylated product of the enzymatic reaction as compared to the substrate, which allows the assay to be carried out in the product-selective mode. The final product incorporates a trimethylammonium moiety, a known high-affinity binding motif for CX4. Two substrates corresponding to the H3 N-terminal tail, namely, S2 (RTKQTARKSTGGKAP) and S6 (QTARKSTGGS), were selected as model compounds for methylation with the Neurospora crassa Dim-5 enzyme and investigated by the newly developed supramolecular tandem HKMTs assay. Only the longer substrate S2 underwent methylation in solution. The potential of the assay for inhibitor screening was demonstrated by means of inhibition studies with 1,10-phenanthroline to afford an inhibition constant of (70±20) μM.

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