Insights into the Destabilizing Effect of Fluorinated Ethanol on Biomimetic Membranes

The ability of alcohols to perturb the structure and function of membrane bilayers and membrane proteins has made them indispensable in the pharmaceutical and biochemical industry. In the present study, we delineate the bilayer-modifying potency of trifluoroethanol (TFE), a fluorinated analogue of widely used ethanol (EtOH), toward biomimetic lipid membranes composed of pure 1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphocholine (POPC) and POPC/cholesterol (POPC/CHOL) lipids using experimental techniques and atomistic molecular dynamics simulations. Our field emission scanning electron microscopy results show the appearance of small particles on the surface of POPC liposome in the presence of 60 v/v% EtOH or TFE, which is otherwise smooth, indicating alcohol-mediated structural modification in the liposome. Dynamic light scattering measurements reveal liposome enlargement at the lower alcohol concentrations and the presence of smaller globules at high concentrations of TFE. The simulation results reveal that the POPC bilayer with TFE suffers the highest degree of perturbation (complete rupture) beyond 50 v/v% concentration, followed by POPC/CHOL-TFE, POPC-EtOH systems, and binary POPC/CHOL bilayer with ethanol partially retaining its bilayer structure at a given concentration. Lipid tail order parameters reveal that TFE induces more disorder in lipids than EtOH for both the POPC and POPC/CHOL systems. Density profiles along the bilayer normal show the loss of bilayer structure with increasing alcohol concentration, with TFE mediating a higher degree of structural disruption at the same concentrations. The higher detrimental impact of TFE on lipid bilayers is attributed to extensive H-bonding and stronger attractive nonpolar interaction between lipid and TFE molecules, leading to weaker lipid-lipid interaction in the presence of TFE and exceptionally high TFE-TFE electrostatic repulsion when compared to its nonfluorinated counterpart.