Ion pairing in aqueous tetramethylammonium–acetate solutions by neutron scattering and molecular dynamics simulations

Tetramethylammonium (TMA) is a ubiquitous cationic motif in biochemistry, found in the charged choline headgroup of membrane phospholipids and in tri-methylated lysine residues, which modulates histone-DNA interactions and impacts epigenetic mechanisms. TMA interactions with anionic species, particularly carboxylate groups of amino acid residues and extracellular sugars, are of substantial biological relevance, as these interactions mediate a wide range of cellular processes. This study investigates the molecular interactions between TMA and acetate, representing carboxylate-containing groups, using neutron scattering experiments complemented by force fields and <i>ab initio</i> molecular dynamics (MD) simulations. Neutron diffraction with isotopic substitution reveals specific ion pairing signatures between TMA and acetate, with simulations providing a detailed interpretation of the ion pairing structures. Force fields, notably CHARMM36 with the electronic continuum correction (ECC) (by a factor of 0.85) and AMBER99SB, capture essential pairing characteristics, but only revPBE-based <i>ab initio</i> MD simulations accurately model specific experimental features such as the low <i>Q</i> peak intensity in reciprocal space. Our study delivers a refined molecular model of TMA-carboxylate interactions, guiding the selection of force fields for complex biological systems where such interactions are of significant importance.