According to the evaluation based on lipid headgroup order parameter changes, etidocaine and TPP binding affinities to a POPC membrane were slightly underestimated or close to experiments in simulations with standard CHARMM36-based force field parameters. This is in contrast with previous studies for sodium and calcium ions, where binding affinities were typically overestimated by canonical force fields. Therefore, our results suggest that force fields do not generally overestimate the binding of all positively charged molecules to membranes. Furthermore, the implicit inclusion of electronic polarizability using ECC increased the binding affinities of etidocaine and TPP to a POPC membrane, whereas calcium is known to behave oppositely. These observations can be explained by the different binding mechanisms of calcium and the small molecules with hydrophobic moieties. Calcium binds to the lipid phosphate oxygens via direct electrostatic interactions. The binding of small molecules is, on the other hand, driven by hydrophobic interactions. While ECC reduces the direct attraction between lipids and ions, it also reduces the solubility to water, which is more important for small molecules. Different binding mechanisms also explain the deeper penetration of etidocaine and TPP into the membrane core than calcium ions.