Issue 26, 2023

Limitations of non-polarizable force fields in describing anion binding poses in non-polar synthetic hosts

Abstract

Transmembrane anion transport by synthetic ionophores has received increasing interest not only because of its relevance for understanding endogenous anion transport, but also because of potential implications for therapeutic routes in disease states where chloride transport is impaired. Computational studies can shed light on the binding recognition process and can deepen our mechanistic understanding of them. However, the ability of molecular mechanics methods to properly capture solvation and binding properties of anions is known to be challenging. Consequently, polarizable models have been suggested to improve the accuracy of such calculations. In this study, we calculate binding free energies for different anions to the synthetic ionophore, biotin[6]uril hexamethyl ester in acetonitrile and to biotin[6]uril hexaacid in water by employing non-polarizable and polarizable force fields. Anion binding shows strong solvent dependency consistent with experimental studies. In water, the binding strengths are iodide > bromide > chloride, and reversed in acetonitrile. These trends are well captured by both classes of force fields. However, the free energy profiles obtained from potential of mean force calculations and preferred binding positions of anions depend on the treatment of electrostatics. Results from simulations using the AMOEBA force-field, which recapitulate the observed binding positions, suggest strong effects from multipoles dominate with a smaller contribution from polarization. The oxidation status of the macrocycle was also found to influence anion recognition in water. Overall, these results have implications for the understanding of anion host interactions not just in synthetic ionophores, but also in narrow cavities of biological ion channels.

Graphical abstract: Limitations of non-polarizable force fields in describing anion binding poses in non-polar synthetic hosts

Associated articles

Supplementary files

Article information

Article type
Paper
Submitted
30 Jan 2023
Accepted
20 Jun 2023
First published
20 Jun 2023
This article is Open Access
Creative Commons BY license

Phys. Chem. Chem. Phys., 2023,25, 17596-17608

Limitations of non-polarizable force fields in describing anion binding poses in non-polar synthetic hosts

D. Seiferth, S. J. Tucker and P. C. Biggin, Phys. Chem. Chem. Phys., 2023, 25, 17596 DOI: 10.1039/D3CP00479A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements