While the global minimum free energy conformation is still reached when the chromophore resides in the water bulk, a slightly deeper minimum at the polar head regions can be observed for this isomer. Hence, once again a metastable state can be formed, which is however due to the opposite isomer compared to the natural compound. Anyway, if we consider the free energy barriers, the membrane-bound state should again be short-lived. As of note the CyP compound have been shown to possess highly improved photophysical and photochemical properties compared to the natural one, particularly in terms of photoisomerization efficiency and quantum yield. Hence, only a rather limited interaction with the lipid bilayers may be highlighted, a situation which in turn will be detrimental for LAT applications. A possible way to overcome these limitations would be via the functionalization of the most suitable CyP with a hydrophobic lateral group such as n-butyl (CyP-OBu), as shown in Figure . This structural modification totally changes the free energy landscape, especially for the E-isomer.