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.

Exploring Covalent Allosteric Inhibition of Antigen 85C from Mycobacterium tuberculosis by Ebselen Derivatives

“…The calculated interaction energies for Arg239-ebselen suggest more favorable interactions than guanidinium-benzene. 21 Again, the more favorable interactions can be attributed to additional electrostatic, dispersion, and inductive interactions from other chemical moieties within ebselen but are not characterized here. Considering Arg-benzene (i.e., cation— π ) interactions specifically, our computed values are closer to those of the parallel Arg-benzene orientation than those for the perpendicular orientation, which are −8.6 and −14.9 kcal/mol, respectively.…”

“…Considering Arg-benzene (i.e., cation— π ) interactions specifically, our computed values are closer to those of the parallel Arg-benzene orientation than those for the perpendicular orientation, which are −8.6 and −14.9 kcal/mol, respectively. 21,22 The parallel interaction orientation has been previously shown to be favorably formed in solution. 23 …”

The Cation−π Interaction Enables a Halo-Tag Fluorogenic Probe for Fast No-Wash Live Cell Imaging and Gel-Free Protein Quantification

“…It is well established that fluorination of a benzene ring reduces its negative charge and compromises the cation−π interaction. 59−61 To this end, we incorporated 5-fluorotryptophan [5FW (Figure 4a)] into the Halo protein during its biosynthesis by inducing protein expression in an E. coli tryptophan auxotroph in the presence of excess 5FW. 50 Mass spectrometry data showed that 67% of the purified 5FW-Halo protein incorporated 5FW for all nine tryptophan residues (Figure 4b).…”

Investigation of Trimethyllysine Binding by the HP1 Chromodomain via Unnatural Amino Acid Mutagenesis

“…E int values were calculated at the M06/6-31G(d,p) level of theory (see SI), which has previously been shown to predict cation–π strength in good agreement with experimental gas-phase measurements for tetramethylammonium interactions with benzene. 30 Calculated E int values predict a stronger interaction with Kme3 for Tyr24 ( E int = −11.6 kcal/mol) when compared to Tyr48 ( E int = −6.9 kcal/mol; Figure 3B,C). Furthermore, calculations at the M06 level performed using the larger 6-311+G(d,p) basis set provided similar results (Tyr24- E int = −11.0 kcal/mol; Tyr48- E int = −7.2 kcal/mol).…”

“…30 Expressions in the absence of amino acid yielded little to no HP1; however, addition of 5–20 mM p CNPhe, p NO 2 Phe, p CF 3 Phe, or p CH 3 Phe led to high levels of UAA containing protein (Figure S1). Although p CNPheRS has been shown to incorporate CN- and NO 2 -substituted Phe, 26 to our knowledge this is the first demonstration of promiscuous p CNPheRS-mediated incorporation of p CF 3 Phe, and p CH 3 Phe.…”