In our case, and coherently with previous studies, we have chosen as collective variable the distance between the centers of mass of the drug and of the lipid bilayer projected on the axis parallel to the membrane. The results of the free energy profiles (FEP) are reported in Figure where it is evidenced that in the case of the natural cyclocurcumin both Z and E-isomers present a free energy penalty for their penetration inside the membrane. As a matter of fact, while a very shallow free energy minimum of about 2 kcal/mol is observed at the polar head water interface for both isomers, the FEP profile of the E cyclocurcumin increases steadily reaching more than 25 kcal/mol at the center of the lipid bilayer. Only a flat region, at around 15-20 angstrom distance from the center can be observed, corresponding to a slight stabilization at the polar head/hydrophobic core region. The Z-isomer presents a globally similar profile, however the free energy barrier for the membrane penetration is now reduced to about 15 kcal/mol, and more importantly, a minimum appears at the polar head/hydrophobic core region indicative of a metastable state. However, this conformation can be reached overcoming a 5 kcal/mol from the polar head/water region and is most likely extremely short lived.