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Cation-π Interactions: Computational Analyses of the Aromatic Box Motif and the Fluorination Strategy for Experimental Evaluation of Cys-Loop Receptors and Related Structures

Davis, Matthew R. and Dougherty, Dennis A. (2016) Cation-π Interactions: Computational Analyses of the Aromatic Box Motif and the Fluorination Strategy for Experimental Evaluation of Cys-Loop Receptors and Related Structures. Biophysical Journal, 110 (3). 454A. ISSN 0006-3495. http://resolver.caltech.edu/CaltechAUTHORS:20160606-085021438

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Abstract

Cation-π interactions are common in biological systems, in particular ligand-gated ion channels (LGICs). Our own studies, in addition to more recent structural studies, have revealed the aromatic box as a common motif for binding cationic ligands. With the aim of understanding the nature of the aromatic box, several computational methods were evaluated for their ability to reproduce experimental cation-π binding energies. We find the DFT method M06 with the 6-31G(d,p) basis set performs best of several methods tested. The binding of benzene to a number of different cations (sodium, potassium, ammonium, tetramethylammonium, and guanidinium) was studied. In addition, the binding of the organic cations ammonium and tetramethylammonium to ab initio generated aromatic boxes as well as examples of aromatic boxes from a number of protein crystal structures was investigated. In addition, we have performed a study of the intrinsic distance dependence of the cation-π interaction. We find that multiple aromatic residues can contribute to cation binding in a variety of LGICs including ELIC, the glycine receptor, the GABA(A) receptor, and a model of the nicotinic acetylcholine receptor. Progressive fluorination of benzene and indole was studied as well, and binding energies obtained were used to reaffirm the validity of the “fluorination strategy” to study cation-π interactions in vivo.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.bpj.2015.11.2434DOIArticle
http://www.sciencedirect.com/science/article/pii/S0006349515036176PublisherArticle
ORCID:
AuthorORCID
Davis, Matthew R.0000-0002-6374-4555
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2016 Biophysical Society. Published by Elsevier Inc.
Record Number:CaltechAUTHORS:20160606-085021438
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160606-085021438
Official Citation:Matthew R. Davis, Dennis A. Dougherty, Cation-π Interactions: Computational Analyses of the Aromatic Box Motif and the Fluorination Strategy for Experimental Evaluation of Cys-Loop Receptors and Related Structures, Biophysical Journal, Volume 110, Issue 3, Supplement 1, 16 February 2016, Page 454a, ISSN 0006-3495, http://dx.doi.org/10.1016/j.bpj.2015.11.2434. (http://www.sciencedirect.com/science/article/pii/S0006349515036176)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:67680
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:06 Jun 2016 16:25
Last Modified:26 Oct 2017 22:28

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