Triptycene-Based Lipid Mimics for Thermally Stable Membrane Phase Separation.

Membrane phase separation enables the formation of laterally compartmentalized domains with distinct local environments in lipid bilayers. Such compartmentalization offers a strategy for functional membrane materials because clustered molecules can exhibit properties that differ from those of uniformly mixed membranes. Despite this potential, the induction of thermally stable domains in fluid lipid bilayers remains a challenge owing to the high miscibility of lipid molecules. Here, we report triptycene-based lipid mimics that induce thermally stable membrane phase separation. Using the triple cycloaddition of ynolates with benzynes, we prepared amphiphilic triptycene derivatives bearing hydrophobic alkyl chains and hydrophilic headgroups. Among them, trialkyl-substituted triptycene (lipid mimic C) induces phase separation and thus, C-rich domain formation in dimyristoylphosphatidylcholine (DMPC) bilayers. X-ray diffraction analysis revealed that the C-rich domains consist of 2:1 DMPC:C and preserve gel-phase-like lipid packing at 30 °C. Moreover, the C-rich domains exhibit exceptional thermal stability because the C-rich/C-poor phase separation persists up to 58 °C. Calorimetry and fluorescence observations indicated that DMPC/C bilayers undergo fluid/fluid phase separation, which is rare phenomena in binary lipid mixtures, around 50 °C. Monolayer measurements suggested the embedding of triptycene units and lipid molecules into the interblade spaces of the triptycene. These results indicate that domain stabilization arises from a dual embedding mechanism: interdigitation between neighboring triptycene frameworks and the cooperative incorporation of surrounding lipid molecules into the grooves of triptycene. This study established a design principle for thermally stable artificial membrane domains and provided a platform for compartmentalized membrane materials that can exploit the clustering effects of functional molecules.