The combination of the required large simulation boxes with the slow equilibration times makes simulations unfeasible for some strongly bound molecules. For example, bulk concentrations of SMS peptide are in the sub-millimolar range in experiments which would require approximately 200 000 water molecules per peptide in simulations. On the other hand, binding or unbinding events were not observed for dibucaine during the 1 360 ns simulation. Nevertheless, for etidocaine and TPP, the binding dynamic was sufficiently fast to enable to equilibrate the simulations within feasible time (1-5 µs) and simulation box z-dimension (12-80 nm) scales (Figs. S4 and S5 in the SI). Therefore, we proceeded to evaluate the binding affinities of these molecules in MD simulations to membranes against the available lipid headgroup order parameter data.