In conclusion, none of the parameters generated with the standard approaches for etidocaine or TPP predicted the overbinding of these molecules to POPC membranes, while some parameters predicted too weak binding affinity. Therefore, our results suggest that the previously observed overbinding of sodium and calcium ions to membranes in canonical MD simulation force fields is not a general feature for all positively charged biomolecules. Changes in the POPC headgroup α-carbon order parameters as a function of small molecule concentration with respect to water from simulations and experiments for etidocaine and TPP. Error bars from simulations are not visible for most order parameters as they are smaller than the point size.