Perturbation of Lipid Bilayers by Biomimetic Photoswitches Based on Cyclocurcumin

The use of photoswitches which may be activated by suitable electromagnetic radiation is an attractive alternative to conventional photodynamic therapy. Here, we report all-atom molecular dynamics simulation of a biomimetic photoswitch derived from cyclocurcumin and experiencing E/Z photoisomerization. In particular, we show that the two isomers interact persistently with a lipid bilayer modeling a cellular membrane. Furthermore, the interaction with the membrane is strongly dependent on the concentration, and a transition between ordered and disordered arrangements of the photoswitches is observed. We also confirm that the structural parameters of the bilayer are differently affected by the two isomers and hence can be modulated through photoswitching, offering interesting perspectives for future applications

Intramolecular Interactions versus Hydration Effects on <i>p</i>‑Guanidinoethyl-phenol Structure and p<i>K</i>_a Values

We analyze the structure, hydration, and p<i>K</i>_a values of <i>p</i>-guanidinoethyl-phenol through a combined experimental and theoretical study. These issues are relevant to understand the mechanism of action of the tetrameric form, the antibacterial compound tetra-<i>p</i>-guanidinoethyl-calix­[4]­arene (Cx1). The investigated system can also be useful to model other pharmaceutical drugs bearing a guanidine function in the vicinity of an ionizable group and the effect of arginine on the p<i>K</i>_a of vicinal ionizable residues (in particular tyrosine) in peptides. The <i>p</i>-guanidinoethyl-phenol monomer (mCx1) has two ionizable groups. One important particularity of this system is that it exhibits high molecular flexibility that potentially leads to enhanced stabilization in folded structures by direct, strong Coulombic interactions between the ionizable groups. The first p<i>K</i>_a corresponding to ionization of the −OH group has experimentally been shown to be only slightly different from usual values in substituted phenols. However, because of short-range Coulombic interactions, the role of intramolecular interactions and solvation effects on the acidities of this compound is expected to be important and it has been analyzed here on the basis of theoretical calculations. We use a discrete-continuum solvation model together with quantum-mechanical calculations at the B3LYP level of theory and the extended 6-311+G­(2df,2p) basis set. Both intra- and intermolecular effects are very large (∼70 kcal/mol) but exhibit an almost perfect compensation, thus explaining that the actual p<i>K</i>_a of mCx1 is close to free phenol. The same compensation of environmental effects applies to the second p<i>K</i>_a that concerns the guanidinium group. Such a p<i>K</i>_a could not be determined experimentally with standard titration techniques and in fact the theoretical study predicts a value of 14.2, that is, one unit above the p<i>K</i>_a of the parent ethyl-guanidinium molecule

Biomimetic Photo-Switches Softening Model Lipid Membranes

We report the synthesis and characterization of a novel photo-switch based on biomimetic cyclocurcumin analogous and interacting with the lipid bilayer, which can be used in the framework of oxygen-independent light-induced therapy. More specifically, by using molecular dynamics simulations and free energy techniques, we show that the inclusion of hydrophobic substituents is needed to allow insertion in the lipid membrane. After having confirmed experimentally that the substituents do not preclude the efficient photoisomerization, we show through UV–vis and dynamic light scattering measurements together with compression isotherms that the chromophore is internalized in both lipid vesicles and monomolecular film, respectively, inducing their fluidification. The irradiation of the chromophore-loaded lipid aggregates modifies their properties due to the different organization of the two diastereoisomers, E and Z. In particular, a competition between a fast structural reorganization and a slower expulsion of the chromophore after isomerization can be observed in the kinetic profiles recorded during E to Z photoisomerization. This report paves the way for future investigations in the optimization of biomimetic photoswitches potentially useful in modern light-induced therapeutic strategies