This tutorial review summarizes the continuining exploration of three prominent water-soluble hosts: cucurbiturils, pillar[n]arenes and deep-cavity cavitands. As we describe, these hosts are revealing how orchestrating the Hydrophobic Effect can lead to a broad range of properties and applications, from: nano-reactors, supramolecular polymers, stimuli-responsive biointerfaces, switches, and novel purification devices. We also describe how their study is also revealing more details about the properties of water and aqueous solutions.

The synthesis of a water-soluble, deep-cavity cavitand is reported. A blend of molecular curvature and amphiphilicity, this molecule has a hydrophobic concave surface and a hydrophilic convex surface. As a result, in aqueous solution and in the presence of a guest molecule, the host self-assembles to form a capsular assembly with an interior cavity large enough to entrap steroidal guests.

Calix[n]arenes (n = 4, 5, 6, 8) are "chalicelike" phenol-based macrocycles that are among the most fascinating and highly studied scaffolds in supramolecular chemistry. This stems from the functional and tunable diversity at both their upper and lower rims, their preorganized nonpolar cavities and preorganized ionbinding sites, and their well-defined conformations. Conjugation of calixarene scaffolds with various fluorogenic groups has led to the development of smart fluorescent probes that have been utilized as molecular sensors, in bioimaging, for drug and gene delivery, in self-assembly/aggregation, and as smart materials. The fine-tuning and incorporation of different ligating sites in the calix[4]arene scaffold have produced numerous molecular sensors for cations, anions, and biomolecules. Moreover, the aqueous solubility of p-sulfonatocalix[4]arenes has engendered their potential use in drug/gene delivery and enzymatic assays. In addition, because of their strong optical properties, fluorescent calix[4]arenes have been used to develop smart materials, including gels as well as nonlinear optical, organic light-emitting diode, and multiphoton materials. Finally, significant developments in the utility of fluorescent higher calixarenes have been made for bioapplications. This review critically summarizes the recent advances made in all of these different areas.

For over 120 years it has been appreciated that certain salts (kosmotropes) cause the precipitation of proteins, whilst others (chaotropes) increase their solubility. The cause of this, “Hofmeister effect” is still unclear; especially with the original concept that kosmotropic anions “make” water structure and chaotropes “break” it being countered by recent studies suggesting otherwise. Here, we present the first direct evidence that chaotropic anions have an affinity for hydrophobic concavity, and that it is competition between a convex hydrophobe and the anion for a binding site that leads to the apparent weakening of the hydrophobic effect by chaotropes. In combination, these results suggest that chaotropes primarily induce protein solubilization by direct binding to concavity in the molten globule state of a protein.

Accurately predicting the binding affinities of small organic molecules to biological macro-molecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macro-molecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host-guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host-guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from 10 participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host-guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host-guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host-guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states) may be required to further enhance predictive accuracy.