Cation-π Interactions between Quaternary Ammonium Ions and Amino Acid Aromatic Groups in Aqueous Solution

Cation-π interactions play important roles in the stabilization of protein structures and protein-ligand complexes. They contribute to the binding of quaternary ammonium ligands (mainly RNH₃⁺ and RN(CH₃)₃⁺) to various protein receptors and are likely involved in the blockage of potassium channels by tetramethylammonium (TMA⁺) and tetraethylammonium (TEA⁺). Polarizable molecular models are calibrated for NH₄⁺, TMA⁺, and TEA⁺ interacting with benzene, toluene, 4-methylphenol, and 3-methylindole (representing aromatic amino acid side chains) based on the ab initio MP2(full)/6-311++G(d,p) properties of the complexes. Whereas the gas-phase affinity of the ions with a given aromatic follows the trend NH₄⁺ > TMA⁺ > TEA⁺, molecular dynamics simulations using the polarizable models show a reverse trend in water, likely due to a contribution from the hydrophobic effect. This reversed trend follows the solubility of aromatic hydrocarbons in quaternary ammonium salt solutions, which suggests a role for cation-π interactions in the salting-in of aromatic compounds in solution. Simulations in water show that the complexes possess binding free energies ranging from -1.3 to -3.3 kcal/mol (compared to gas-phase binding energies between -8.5 and -25.0 kcal/mol). Interestingly, whereas the most stable complexes involve TEA⁺ (the largest ion), the most stable solvent-separated complexes involve TMA⁺ (the intermediate-size ion).