Modelling the effects of E/Z photoisomerization of a cyclocurcumin analogue on the properties of cellular lipid membranes

The use of photosensitive molecules capable of isomerizing under light stimuli, and thus induce perturbation in biological systems, is becoming increasingly popular for potential light-activated chemotherapeutic purposes. We recently show that a cyclocurcumin derivative (CCBu), may be suitable for light-activated chemotherapy and may constitute a valuable alternative to traditional photodynamic therapy, due to its oxygen-independent mechanism of action, which allows the treatment of hypoxic solid tumors. In particular, we have shown that the E/Z photoisomerization of CCBu correlates with strong perturbations of model lipid bilayers. In this work, we perform all-atom classical molecular dynamics for a more complex bilayer, whose composition is, thus, much closer to eukaryotic outer cell membranes. We have evidenced important differences in the interaction pathway between CCBu and the complex lipid bilayer as compared to previous models, concerning both the membrane penetration capacity and the isomerization-induced perturbations. While we confirm that structural perturbations of the lipid membrane are induced by isomerization, we also show how the use of a simplified membrane model can result in an oversimplification of the system and hinder key physical and biological phenomena. Although, CCBu may be considered as a suitable candidate for light-activated chemotherapy, we also underline how the inclusion of bulkier substituents, inducing larger perturbations upon photoisomerization, may enhance its efficiency.

Automated summary

The use of photosensitive molecules for light-activated chemotherapy is gaining popularity. A cyclocurcumin derivative (CCBu) has been identified as a potential alternative to traditional photodynamic therapy, showing oxygen-independent mechanism and effectiveness against hypoxic solid tumors. The interaction between CCBu and complex lipid bilayers has been studied using molecular dynamics, revealing differences in membrane penetration and isomerization-induced perturbations. Simplified membrane models oversimplify the system and hinder important physical and biological phenomena. Addition of bulkier substituents to CCBu can enhance its efficiency.