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Counteranions at Peripheral Sites Tune Guest Affinity for a Protonated Hemicryptophane.

ABSTRACT: The affinity of small molecules for biomolecular cavities is tuned through a combination of primary and secondary interactions. It has been challenging to mimic these features in organic synthetic host molecules, however, where the cavities tend to be highly symmetric and nonpolar, and less amenable to chemical manipulation. Here, a host molecule composed of a TREN ligand and cyclotriveratrylene moiety was investigated. Size-matched polar guests were encapsulated within the cavity via triple protonation of the TREN moiety with various sulfonic acids. X-ray crystallography confirmed guest encapsulation and identified three methanesulfonates, p-toluenesulfonates, or 2-naphthalenesulfonates hydrogen-bonded with H₃TREN at the periphery of the cavity. These structurally diverse counteranions were shown by ¹H NMR spectroscopy to differentially regulate guest access at the three portals, and to undergo competitive displacement in solution. This work reveals "counteranion tuning" to be a simple and powerful strategy for modulating host-guest affinity, as applied here in a TREN-hemicryptophane.

SUBMITTER: Lin Y

PROVIDER: S-EPMC9017572 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Counteranions at Peripheral Sites Tune Guest Affinity for a Protonated Hemicryptophane.

Lin Yannan Y Gau Michael R MR Carroll Patrick J PJ Dmochowski Ivan J IJ

The Journal of organic chemistry 20220325 8

The affinity of small molecules for biomolecular cavities is tuned through a combination of primary and secondary interactions. It has been challenging to mimic these features in organic synthetic host molecules, however, where the cavities tend to be highly symmetric and nonpolar, and less amenable to chemical manipulation. Here, a host molecule composed of a TREN ligand and cyclotriveratrylene moiety was investigated. Size-matched polar guests were encapsulated within the cavity via triple pro ...[more]

PMID: 35333529

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Project description:Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host-guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host-guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from ten participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host-guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host-guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host-guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states), may be required to further enhance predictive accuracy.

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Counteranions at Peripheral Sites Tune Guest Affinity for a Protonated Hemicryptophane.

Publications

Counteranions at Peripheral Sites Tune Guest Affinity for a Protonated Hemicryptophane.

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