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Octa-acid (OA) and tetra- endo -methyl octa-acid (TEMOA) are deep cavity cavitands that readily form multimeric complexes with hydrophobic guests, like n -alkanes, in aqueous solution. Experimentally, OA displays a monotonic progression from monomeric to dimeric complexes with n -alkanes of increasing length, while TEMOA exhibits a non-monotonic progression from monomeric, to dimeric, to monomeric, to dimeric complexes over the same range of guest sizes. Previously we have conducted simulations demonstrating this curious behavior arises from the methyl units ringing TEMOA's portal to its hydrophobic pocket barring the possibility for two alkane chains to simultaneously bridge between two hosts in a dimer. Here we expand our prior simulation study to consider the partially methylated hosts mono- endo -methyl octa-acid, 1,3-di- endo -methyl octa-acid, and tri- endo -methyl octa-acid to examine the emergence of non-monotonic assembly behavior. Our simulations demonstrate a systematic progression of non-monotonic assembly with increasing portal methylation. This behavior is traced to the progressive destabilization of 2 : 2 complexes (two hosts assembled with two guests) rather than stabilizing other potential host/guest complexes that could be formed. 

Hydrophobic interactions drive the binding of nonpolar ligands to the oily pockets of proteins and supramolecular species in aqueous solution. As such, the wetting of host pockets is expected to play a critical role in determining the thermodynamics of guest binding. Here we use molecular simulations to examine the impact of pressure on the wetting and dewetting of the nonpolar pockets of a series of deep-cavity cavitands in water. The portals to the cavitand pockets are functionalized with both nonpolar (methyl) and polar (hydroxyl) groups oriented pointing either upward or inward toward the pocket. We find wetting of the pocket is favored by the hydroxyl groups and dewetting is favored by the methyl groups. The distribution of waters in the pocket is found to exhibit a two-state-like equilibrium between wet and dry states with a free energy barrier between the two states. Moreover, we demonstrate that the pocket hydration of the cavitands can be collapsed onto a unified adsorption isotherm by assuming the effective pressures within each cavitand pocket differ by a shift pressure that depends on the chemical identity and number of functional groups placed about the portal. These observations support the development of a twostate capillary evaporation model that accurately describes the equilibrium between states and naturally gives rise to the effective shift pressures observed from simulation. This work demonstrates that the hydration of host pockets can be tuned following simple design rules that in turn are expected to impact the thermodynamics of guest complexation. 

We describe the use of a supramolecular nano-capsule for selective protection of cis - and trans -C18 mono-unsaturated fatty-acid esters. In contrast to earlier studies revealing that protection of smaller esters is dictated by affinity, protection of these larger esters was found to be dependent on the packing motif of the guest. 

There are many open questions regarding the hydration of solvent-exposed, non-polar tracts and pockets in proteins. Although water is predicted to de-wet purely repulsive surfaces and evacuate crevices, the extent of de-wetting is unclear when ubiquitous van der Waals interactions are in play. The structural simplicity of synthetic supramolecular hosts imbues them with considerable potential to address this issue. To this end, here we detail a combination of densimetry and molecular dynamics simulations of three cavitands, coupled with calorimetric studies of their complexes with short-chain carboxylates. Our results reveal the range of wettability possible within the ostensibly identical cavitand pockets — which differ only in the presence/position of the methyl groups that encircle the portal to their non-polar pockets. The results demonstrate the ability of macrocycles to template water cavitation within their binding sites and show how the orientation of methyl groups can trigger the drying of non-polar pockets in liquid water, suggesting new avenues to control guest complexation. 

Science still does not have the ability to accurately predict the affinity that ligands have for proteins. In an attempt to address this, the Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) series of blind predictive challenges is a community-wide exercise aimed at advancing computational techniques as standard predictive tools in rational drug design. In each cycle, a range of biologically relevant systems of different levels of complexity are selected to test the latest modeling methods. As part of this on-going exercise, and as a step towards understanding the important factors in context dependent guest binding, we challenged the computational community to determine the affinity of a series of negatively and positively charged guests to two constitutionally isomeric cavitand hosts: octa-acid 1 , and exo -octa acid 2 . Our affinity determinations, combined with molecular dynamics simulations, reveal asymmetries in affinities between host–guest pairs that cannot alone be explained by simple coulombic interactions, but also point to the importance of host–water interactions. Our work reveals the key facets of molecular recognition in water, emphasizes where improvements need to be made in modelling, and shed light on the complex problem of ligand-protein binding in the aqueous realm.