Charged small molecule binding to membranes in MD simulations evaluated against NMR experiments

Interactions of charged molecules with biomembranes regulate many of their biological activities, but their binding affinities to lipid bilayers are difficult to measure experimentally and model theoretically. Classical molecular dynamics (MD) simulations have potential to capture the complex interactions determining how charged biomolecules interact with membranes, but systematic overbinding of sodium and calcium cations in standard MD simulations raises a question how accurately force fields capture the interactions between lipid membranes and charged biomolecules. Here, we evaluate the binding of positively charged small molecules, Etidocaine and tetraphenylphosphonium (TPP), to a POPC lipid bilayer using the changes in lipid headgroup order parameters. Because the binding of these molecules is driven hydrophobic effects rather than direct electrostatic interactions, their binding affinities are not overestimated by standard force field parameters, implicit inclusion of electronic polarizability increases their binding affinity, and they penetrate into the hydrophobic membrane core, in contrast to calcium and sodium ions. Furthermore, our results elucidate the relative binding affinities between different charged biomolecules and delivers tools for further development of MD simulation parameters and methodology.