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Elucidating dissociation activation energies in host-guest assemblies featuring fast exchange dynamics.

ABSTRACT: The ability to mediate the kinetic properties and dissociation activation energies (E _a) of bound guests by controlling the characteristics of "supramolecular lids" in host-guest molecular systems is essential for both their design and performance. While the synthesis of such systems is well advanced, the experimental quantification of their kinetic parameters, particularly in systems experiencing fast association and dissociation dynamics, has been very difficult or impossible with the established methods at hand. Here, we demonstrate the utility of the NMR-based guest exchange saturation transfer (GEST) approach for quantifying the dissociation exchange rates (k _out) and activation energy (E _a,out) in host-guest systems featuring fast dissociation dynamics. Our assessment of the effect of different monovalent cations on the extracted E _a,out in cucurbit[7]uril:guest systems with very fast k _out highlights their role as "supramolecular lids" in mediating a guest's dissociation E _a. We envision that GEST could be further extended to study kinetic parameters in other supramolecular systems characterized by fast kinetic properties and to design novel switchable host-guest assemblies.

SUBMITTER: Shusterman-Krush R

PROVIDER: S-EPMC8179218 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We have tried to calculate the free energy for the binding of six small ligands to two variants of the octa-acid deep cavitand host in the SAMPL5 blind challenge. We employed structures minimised with dispersion-corrected density-functional theory with small basis sets and energies were calculated using large basis sets. Solvation energies were calculated with continuum methods and thermostatistical corrections were obtained from frequencies calculated at the HF-3c level. Care was taken to minimise the effects of the flexibility of the host by keeping the complexes as symmetric and similar as possible. In some calculations, the large net charge of the host was reduced by removing the propionate and benzoate groups. In addition, the effect of a restricted molecular dynamics sampling of structures was tested. Finally, we tried to improve the energies by using the DLPNO-CCSD(T) approach. Unfortunately, results of quite poor quality were obtained, with no correlation to the experimental data, systematically too positive affinities (by ~50 kJ/mol) and a mean absolute error (after removal of the systematic error) of 11-16 kJ/mol. DLPNO-CCSD(T) did not improve the results, so the accuracy is not limited by the energy function. Instead, four likely sources of errors were identified: first, the minimised structures were often incorrect, owing to the omission of explicit solvent. They could be partly improved by performing the minimisations in a continuum solvent with four water molecules around the charged groups of the ligands. Second, some ligands could bind in several different conformations, requiring sampling of reasonable structures. Third, there is an indication the continuum-solvation model has problems to accurately describe the binding of both the negatively and positively charged guest molecules. Fourth, different methods to calculate the thermostatistical corrections gave results that differed by up to 30 kJ/mol and there is an indication that HF-3c overestimates the entropy term. In conclusion, it is a challenge to calculate binding affinities for this octa-acid system with quantum-mechanical methods.

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Elucidating dissociation activation energies in host-guest assemblies featuring fast exchange dynamics.

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