Neutral Imidazole Lipid Analogues Exhibit Improved Properties for Artificial Model Biomembranes

Pierau, Marco; Kriegler, Simon; Rickhoff, Clara; Paulisch, Tiffany O.; Wegner, Tristan; Alavizargar, Azadeh; Heuer, Andreas; Winter, Roland; Glorius, Frank

Abstract

In recent years, a variety of lipid-mimetic imidazolium salts have been developed and applied to investigate biological membranes and related processes. Despite their overall similar properties to natural lipids, there are potential drawbacks including cytotoxicity attributed to the cationic charge. Herein, we report the investigation of a novel class of electronically neutral imidazole-based lipids. In comparison to their positively charged congeners, they show improved biophysical properties and higher similarity to native lipids. By employing calorimetry, fluorescence spectroscopies, and fluorescence and atomic force microscopy, we examined changes in the thermotropic phase behavior, lipid order parameter, fluidity, and lateral membrane organization upon incorporation of the lipid mimetics. Depending on the characteristic of the lipid chains, charge of the headgroup, and substitution pattern, we observed changes in lipid order and fluidity, thus allowing modulation and fine-tuning of the physicochemical properties of the modified membrane. Notably, a newly synthesized imidazole-based cholesterol showed membrane properties very similar to natural cholesterol. Extensive computational studies indicate effective mimicking of cholesterol and reveal its capability to participate in raft formation. This new class of neutral imidazole lipid analogues is expected to lead to better molecular probes and tools.