Cation–π Interactions in Biomolecular Contexts Studied by Neutron Scattering and Molecular Dynamics: A Case Study of the Tetramethylammonium Cation

Cation–π interactions involving the tetramethylammonium motif are common in biological systems, where they play essential roles in membrane protein function, DNA expression regulation, and protein folding. However, accurately modeling cation–π interactions, where electronic polarization is crucial, presents a significant computational challenge, especially in large biomolecular systems. This study applies a physically justified electronic continuum correction (ECC) to the CHARMM36 force field, scaling ionic charges by a factor of 0.75 to effectively account for electronic polarization without adding computational overhead. While not specifically designed for cation–π interactions, this approach significantly improves predictions of the structure of an aqueous tetramethylammonium–pyridine complex compared to neutron diffraction data. These results, along with computational predictions for the structure of the aqueous tetramethylammonium–phenol complex, highlight the potential of ECC as a versatile method for improving the description of cation–π interactions in biomolecular simulations.