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

ABSTRACT: 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.

SUBMITTER: Barnett JW

PROVIDER: S-EPMC8170693 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Endpoints density functional theory (DFT) provides a framework for calculating the excess chemical potential of a solute in solution using solvent distribution functions obtained from both physical endpoints of a hypothetical charging process which transforms the solvent density from that of the pure liquid to the solution state. In this work, the endpoints DFT equations are formulated in terms of the indirect (solvent-mediated) contribution ω(x) to the solute-solvent potential of mean force, and their connections are established with the conventional DFT expressions which are based on the use of direct correlation functions. ω actually corresponds to the free-energy cost to move a cavity particle (a tagged solvent molecule which interacts with the other solvent molecules but not the solute) from the bulk to the configuration x of a solvent molecule relative to the solute and is a suitable variable to describe the solvent effects on the solute-solvent interactions. HNC and PY type approximations are then used to integrate the DFT charging integral involved in the exact expression for the excess chemical potential. With these approximations, molecular simulations are to be performed at the two endpoints of solute insertion: pure solvent without the solute and the solution system with the fully coupled solute-solvent interaction. An endpoints method thus utilizes the ensembles of intermolecular configurations of physical interest, which are often readily accessible with MD simulations given the present computational power. To illustrate properties of the formulation, we perform simulations of model systems consisting of a cavity particle in an aqueous solution containing a spherical hydrophobic solute of three different sizes from which ω(x) and the solute chemical potential can be calculated using endpoints DFT expressions. These are compared with corresponding results obtained using the approximations needed in order to evaluate the endpoints DFT charging integral when cavity particle simulation data is not available. We analyze a new approximation (two-points quadratic HNC) to the DFT charging integral which captures the correct behavior of the cavity distributions at both endpoints of the solute insertion. The behavior of the cavity particle in simple and complex liquids plays an important role in various theoretical treatments of the solute chemical potential. For pure Lennard-Jones fluids, the free energy to bring a cavity particle from the bulk to the center of a fluid particle is negative. However, for solutes of varying size, this is not generally true for Lennard-Jones fluids or the systems studied in this work. We carry out energetic and structural analyses of the cavity particle in aqueous solution with hydrophobic solutes of varying size and discuss the results in the context of the hydrophobic effect.

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

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