Pressure Induced Wetting and Dewetting of the Nonpolar Pocket of Deep-Cavity Cavitands in Water.

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 two-state 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.

Designing exceptional gas-separation polymer membranes using machine learning.

The field of polymer membrane design is primarily based on empirical observation, which limits discovery of new materials optimized for separating a given gas pair. Instead of relying on exhaustive experimental investigations, we trained a machine learning (ML) algorithm, using a topological, path-based hash of the polymer repeating unit. We used a limited set of experimental gas permeability data for six different gases in ~700 polymeric constructs that have been measured to date to predict the gas-separation behavior of over 11,000 homopolymers not previously tested for these properties. To test the algorithm's accuracy, we synthesized two of the most promising polymer membranes predicted by this approach and found that they exceeded the upper bound for CO2/CH4 separation performance. This ML technique, which is trained using a relatively small body of experimental data (and no simulation data), evidently represents an innovative means of exploring the vast phase space available for polymer membrane design.

Spontaneous drying of non-polar deep-cavity cavitand pockets in aqueous solution.

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 and/or 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, which suggests new avenues to control guest complexation.

Modeling gas transport in polymer-grafted nanoparticle membranes.

We use coarse-grained molecular dynamics simulations to study gas diffusion within nanocomposites consisting of matrix-free polymer-grafted nanoparticles. We compare the transport of gas penetrants in systems using polymer models with and without an angle potential and show that gas diffusion enhancement occurs in nanocomposite systems only with the angle potential. This enhancement is related to the free volume in the system, but the cage size experienced by the gas penetrant seems to be a more relevant indicator of gas diffusion enhancement. The enhancement seen in our simulations is smaller than that observed in experiments.

Alkane guest packing drives switching between multimeric deep-cavity cavitand assembly states.

Alkane guest transfer into aqueous dimeric, tetrameric, hexameric, and octameric assemblies of the deep-cavity cavitand TEMOA is examined using molecular simulations. The experimental transitions between aggregation states strongly correlate with calculated alkane transfer free energy minima, demonstrating the guiding role of guest packing on stabilizing multimeric complexes. The predictive simulation approach described affords a salient rationale as to why octameric assemblies have yet to be experimentally observed.

Connections between the Anomalous Volumetric Properties of Alcohols in Aqueous Solution and the Volume of Hydrophobic Association.

The partial molar volumes of alcohols in water exhibit a non-monotonic dependence on concentration at room temperature, initially decreasing with increasing concentration before passing through a minimum and rising to the pure liquid plateau. This anomalous behavior is associated with hydrophobic interactions. We report molecular simulations of short chain alcohols and alkanes in water to examine the volumetric properties of these mixtures at infinite dilution over a range of temperatures. Our simulations find this anomaly disappears at a crossover temperature, above which the solute volume only varies monotonically with concentration. A Voronoi volume analysis of solution configurations finds that solutes in clusters take up less space than individual solutes at low temperature and more space at elevated temperatures. These changes in cluster volumes are subsequently shown to correlate with the derivative of the solute partial molar volume with respect to solute concentration. The changes in solute volume upon nonpolar solute association impact the response of molecular-scale hydrophobic interactions for assembly with increasing pressure.

Guest Controlled Nonmonotonic Deep Cavity Cavitand Assembly State Switching.

Octa-acid (OA) and tetra-endo-methyl octa-acid (TEMOA) are water-soluble, deep-cavity cavitands with nanometer-sized nonpolar pockets that readily bind complementary guests, such as n-alkanes. Experimentally, OA exhibits a progression of 1:1 to 2:2 to 2:1 host/guest complexes (X:Y where X is the number of hosts and Y is the number of guests) with increasing alkane chain length from methane to tetradecane. Differing from OA only by the addition of four methyl groups ringing the portal of the pocket, TEMOA exhibits a nonmonotonic progression of assembly states from 1:1 to 2:2 to 1:1 to 2:1 with increasing guest length. Here we present a systematic molecular simulation study to parse the molecular and thermodynamic determinants that distinguish the succession of assembly stoichiometries observed for these similar hosts. Potentials of mean force between hosts and guests, determined via umbrella sampling, are used to characterize association free energies. These free energies are subsequently used in a reaction network model to predict the equilibrium distributions of assemblies. Our models accurately reproduce the experimentally observed trends, showing that TEMOA's endo-methyl units constrict the opening of the binding pocket, limiting the conformations available to bound guests and disrupting the balance between monomeric complexes and dimeric capsules. The success of our simulations demonstrate their utility at interpreting the impact of even simple chemical modifications on supramolecular assembly and highlight their potential to aid bottom-up design.

Temperature and pressure dependence of the interfacial free energy against a hard surface in contact with water and decane.

Theoretical descriptions of molecular-scale solvation frequently invoke contributions proportional to the solvent exposed area, under the tacit expectation that those contributions are tied to a surface tension for macroscopic surfaces. Here we examine the application of revised scaled-particle theory (RSPT) to extrapolate molecular simulation results for the wetting of molecular-to-meso-scale repulsive solutes in liquid water and decane to determine the interfacial free energies of hard, flat surfaces. We show that the RSPT yields interfacial free energies at ambient pressures that are consistently greater than that obtained from the liquid-vapor surface tensions of water and decane by ∼4%. Nevertheless, the hard surface and liquid-vapor interfacial free energies are parallel over a broad temperature range at 1 bar indicating similar entropic contributions. With increasing pressure, the hard, flat interfacial free energies exhibit a maximum in the vicinity of ∼1000 bars. This non-monotonic behavior in both water and decane reflects solvent dewetting at low pressures, followed by wetting at higher pressures as the solvents are pushed onto the solute. By comparing the results of RSPT against classic scaled-particle theory (CSPT), we show that CSPT systematically predicts greater entropic penalties for interface formation and makes inconsistent predictions between the pressure dependence of the interfacial free energy and solvent contact density with the solute surface.

Succession of Alkane Conformational Motifs Bound within Hydrophobic Supramolecular Capsular Assemblies.

n-Alkane encapsulation experiments within dimeric octa-acid cavitand capsules in water reveal a succession of packing motifs from extended, to helical, to hairpin, to spinning top structures with increasing chain length. Here, we report a molecular simulation study of alkane conformational preferences within these host-guest assemblies to uncover the factors stabilizing distinct conformers. The simulated alkane conformers follow the trends inferred from 1H NMR experiments, while guest proton chemical shifts evaluated from Gauge Invariant Atomic Orbital calculations provide further evidence our simulations capture guest packing within these assemblies. Analysis of chain length and dihedral distributions indicates that packing under confinement to minimize nonpolar guest and host interior contact with water largely drives the transitions. Mean intramolecular distance maps and transfer free energy differences suggest the extended and helical motifs are members of a larger family of linear guest structures, for which the guest gauche population increases with increasing chain length to accommodate the chains within the complex. Breaks observed between the helical/hairpin and hairpin/spinning top motifs, on the other hand, indicate the hairpin and spinning top conformations are distinct from the linear family. Our results represent the first bridging of empirical and simulation data for flexible guests encapsulated within confined nanospaces, and constitute an effective strategy by which guest packing motifs within artificial or natural compartments can be rationalized and/or predicted a priori.

Hydrated nonpolar solute volumes: Interplay between size, Attractiveness, and molecular structure.

A solute's partial molar volume determines its response to pressure, which can result in changes in molecular conformation or assembly state. Computing speed advances have made accurate partial molar volume evaluation in water routine, allowing for the dissection of the molecular factors underlying this significant thermodynamic variable. A recent simulation analysis of the volumes of nonpolar molecular solutes in water reported that the apparent solvent-free border thickness enshrouding these solutes grows with increasing solute size, based on the assumption the solute can be treated as an individual sphere [Biophys. Chem. 161 (2012) 46]. This suggests the solvent dewets these solutes as they grow in size. Via simulations of dewetted repulsive spherical solutes, we show that the border thicknesses of the largest non-polar molecular solutes tend towards that of a repulsive sphere. When attractive interactions are accounted for, however, the spherical solute border thicknesses fall below that of the largest molecular solutes. We demonstrate that if the molecular solutes are treated with atomic detail rather than approximated as an individual sphere, the border thickness variation is minimal. A geometric model is put forward that reproduces the inferred border thickening, indicating the implied dewetting results from a breakdown in the spherical volume approximation.