In the perspective of LAT based on the modification of the lipid membrane properties by photoswitches, it is essential to characterize the interactions of the drug with the lipid bilayer and the respective and differential effects provoked by the presence of the two isomers in it. To this aim, we first build a lipid bilayer model consisting of Di-Palmitoyl-Phosphatidyl-Choline (DPPC) lipids surrounded by a layer of water and ions to mimic physiological conditions. In a first instance, the natural cyclocurcumin (CC) and our original 2,6-g-pyrone derivative (CyP) have been considered. Note that both these systems involve only shorts methoxy and hydroxy substituents on the peripheric aromatic moieties, while their isomerization performances have been previously studied pointing to the superior performance of the biomimetic CyP analogous compared to CC. The two chromophores have been inserted into the simulation box, and more specifically in the water buffer. Afterwards, classical equilibrium molecular dynamics (MD) simulations have been performed and, while some temporary interaction of the drug with the polar head region appear, no spontaneous penetration into the lipid membrane, or the formation of stable aggregates at the water/membrane interface can be observed, neither for the Z nor the E-isomer. However, the absence of spontaneous penetration in the membrane may be due to kinetic barriers, which cannot be overcome in the timescale spanned by our equilibrium MD simulations but are still compatible with spontaneous physiological processes. Hence, we have performed enhanced sampling on both the Z and E-isomers of CC and CyP interacting with a DPPC bilayer.