Impact of Y³⁺-ions on the structure and phase behavior of phospholipid model membranes

Trivalent yttrium cations are able to mimic the behavior of Ca2+ in many important biochemical processes, and their application in medicinal chemistry has increased in recent years. While the effect of mono- and divalent salts on lipid membranes has been studied extensively, the effect of trivalent cations, such as Y3+, on the structure and phase behavior of lipid bilayers is largely unknown. Here, we studied the effect of YCl3 on the structure, phase behavior and thermodynamic parameters of zwitterionic DPPC, 20% anionic DPPC/DPPG (80/20) and 10% anionic DOPC/DOPG/DPPC/DPPG/cholesterol (20/5/45/5/25) model biomembrane systems using Fourier-transform infrared spectroscopy, differential scanning calorimetry, Laurdan fluorescence spectroscopy, confocal fluorescence microscopy, zeta potential measurements and atomic force microscopy, covering a wide range of salt concentrations, temperature and pressure. Y3+ ions penetrate deep into the lipid headgroup region and are coordinated to the phosphate groups, resulting in a stronger lipid packing and partial dehydration of the headgroup region. Increasing Y3+ concentration leads to a pronounced increase of the gel-to-fluid phase transition temperature of the phospholipid bilayers, owing to an increased lateral compression pressure, particularly for anionic lipid membranes. Increased lipid chain order and phase segregation of anionic membranes is fostered at high salt concentrations owing to lipid sorting. The fluid-to-gel phase transition pressure decreases significantly with the concentration of the trivalent ion, most pronounced for the negatively charged lipid vesicles. Remarkably, the Y3+-induced ordering effect is much stronger than a hydrostatic pressure-induced ordering of the lipid chains.