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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.

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Fig. 1: Chemical structures and illustrations of the deep-cavity cavitand hosts examined.
Fig. 2: Determination of cavitand volumes by measurement of densities of hosts in aqueous solution.
Fig. 3: Molecular simulation prediction of cavitand pocket hydration numbers and volumes.
Fig. 4: Molecular simulation prediction of cavitand pocket drying thermodynamics.

Data availability

The results that appear in Figs. 24 are provided in Source Data Microsoft Excel spreadsheets linked in the HTML version of the article. Data for Supplementary Figs. 16, 18 and 19 are provided in a Microsoft Excel spreadsheet in the Supplementary Data. In addition, we provide GROMACS topology and Gromos87 files for hosts 13 in a .zip file in the Supplementary Data. Additional information supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

M.R.S., T.N. and B.C.G. acknowledge the National Institutes of Health (GM125690) and the National Science Foundation (CHE–1807101) for financial support. B.C.G. and H.S.A. gratefully acknowledge the support of the National Science Foundation (CBET–1403167 and CBET–1805167). J.A.L. and D.B.-A. gratefully acknowledge support from the National Science Foundation (CHE–1763581). J.W.B. gratefully acknowledges financial support from the Louisiana Board of Regents. J.W.B., D.T. and H.S.A. thank the Louisiana Optical Network Initiative who provided computational support.

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Authors

Contributions

J.W.B., D.T., M.R.S. and J.A.L. contributed equally to this publication. J.W.B. and D.T. performed the molecular simulations of the cavitands in water. M.R.S. carried out the described guest-binding thermodynamic determinations with ITC. J.A.L. carried out all the described partial molar volume measurements on hosts 13. T.N. synthesized TEXMOA (3). D.B.-A., B.C.G. and H.S.A. conceived and directed the research and contributed to the data analysis and manuscript preparation.

Corresponding author

Correspondence to Henry S. Ashbaugh.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–33, Tables 1–8 and discussion.

Supplementary Data 1

Data appearing in Supplementary Figs. 16, 18, 19, 21, 22 and 23.

Supplementary Data 2

Zip file of GROMACS topology (.top) and Gromos87 (.gro) files for simulating hosts 1, 2 and 3 in water. GROMACS is a widely used and distributed research software

Source data

Source Data Fig. 2

Experimental densimetry results for cavitand hosts in aqueous solution.

Source Data Fig. 3

Simulation results characterizing the distribution of host occupation probabilities and partial molar volumes as a function of the host pocket occupancy.

Source Data Fig. 4

Free energies of drying host pockets as a function of temperature determined from molecular simulation.

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Barnett, J.W., Sullivan, M.R., Long, J.A. et al. Spontaneous drying of non-polar deep-cavity cavitand pockets in aqueous solution. Nat. Chem. 12, 589–594 (2020). https://doi.org/10.1038/s41557-020-0458-8

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