title: Cation-π interactions: computational analyses of the aromatic box motif and the fluorination strategy for experimental evaluation.
abstract: Cation-π interactions are common in biological systems, and many structural studies have revealed the aromatic box as a common motif. 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 NH4(+) and NMe4(+) to ab initio generated aromatic boxes as well as examples of aromatic boxes from protein crystal structures were investigated. These data, along with a study of the distance dependence of the cation-π interaction, indicate that multiple aromatic residues can meaningfully contribute to cation binding, even with displacements of more than an angstrom from the optimal cation-π interaction. 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.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena CA 91125, USA. dadougherty@caltech.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Davis
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena CA 91125, USA. dadougherty@caltech.edu.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Dougherty
mesh_terms: D064751:Ammonium Compounds / Q000737:chemistry; D001554:Benzene / Q000737:chemistry*; D002412:Cations / Q000737:chemistry; D019791:Guanidine / Q000737:chemistry; D054879:Halogenation; D008958:Models, Molecular; D011188:Potassium / Q000737:chemistry; D012964:Sodium / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D064751:Ammonium Compounds; D002412:Cations; D012964:Sodium; D001554:Benzene; D019791:Guanidine; D011188:Potassium