Search

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). [ABSTRACT FROM AUTHOR]

Cation–π interactions have long been considered a challenge for molecular modelling and a shortcoming of most of the commonly used biomolecular force fields. In this article, we provide an overview of current research on molecular modelling of cation–π interactions, with an emphasis on applications to proteins and on our recent polarisable models based on the classical Drude oscillator. We describe the main approaches used to model cation–π interactions in solution and illustrate their relevance to a few case studies: the stability of the villin headpiece subdomain, the blockade of potassium channels by quaternary ammonium ions, and the permeation of ammonium across transporters of the Amt/MEP family. [ABSTRACT FROM AUTHOR]