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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 | 2020 Dec

REPOSITORIES: biostudies-literature

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

Shusterman-Krush Ronit R Grimm Laura L Avram Liat L Biedermann Frank F Bar-Shir Amnon A

Chemical science 20201208 3

The ability to mediate the kinetic properties and dissociation activation energies (<i>E</i> <sub>a</sub>) 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 ...[more]

PMID: 34163853

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Project description:A grand challenge of computational biophysics is accurate prediction of interactions between molecules. Molecular dynamics (MD) simulations have recently gained much interest as a tool to directly compute rigorous intermolecular binding affinities. The choice of a fixed point-charge or polarizable multipole force field used in MD is a topic of ongoing discussion. To compare alternative methods, we participated in the SAMPL7 and SAMPL8 Gibb octaacid host-guest challenges to assess the Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) polarizable multipole force field. Advantages of AMOEBA over fixed charge models include improved representation of molecular electrostatic potentials and better description of water occupying the unligated host cavity. Prospective predictions for 26 host-guest systems exhibit a mean unsigned error vs experiment of 0.848 kcal/mol across all absolute binding free energies, demonstrating excellent agreement between computational and experimental results. In addition, we explore two topics related to the inclusion of ions in MD simulations: use of a neutral co-alchemical protocol and the effect of salt concentration on binding affinity. Use of the co-alchemical method minimally affects computed energies, but salt concentration significantly perturbs our binding results. Higher salt concentration strengthens binding through classical charge screening. In particular, added Na+ ions screen negatively charged carboxylate groups near the binding cavity, thereby diminishing repulsive coulomb interactions with negatively charged guests. Overall, the AMOEBA results demonstrate the accuracy available through a force field providing a detailed energetic description of the four octaacid hosts and 13 charged organic guests. Use of the AMOEBA polarizable atomic multipole force field in conjunction with an alchemical free energy protocol can achieve chemical accuracy in application to realistic molecular systems.

Dataset Information

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

Publications

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

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