A Bottom-Up Approach to Fungal Plasma Membrane Model: Lipid Mixture Design and Biophysical-Mechanical Characterization

The incidence of invasive fungal diseases has increased, highlighting the necessity for new therapeutic approaches, such as membrane-targeting antifungal agents. These agents demand accurate lipid models for comprehensive molecular-level investigation. In response, the authors devised a consensus five-component fungal plasma membrane model, grounded in lipidomic data, consisting of PC:PE:PI:PA:PS in a 44:29:13:8:6 ratio.

A bottom-up strategy was employed to examine the biophysical characteristics of this system, with a focus on mechanical parameters like bending rigidity and area compressibility. The team achieved this by fusing molecular dynamics simulations with experimental measurements from flicker-noise and ATR-FTIR spectroscopies. Additionally, the researchers explored the influence of two crucial non-phospholipid components, ergosterol and triacylglycerols.

The biophysical examination unveiled that DSPS, interacting specifically with DPPI, induced the most notable deviations in baseline membrane parameters, including area per lipid, membrane thickness, and area compressibility. Conversely, DSPS impacted bending rigidity changes, while DLiPA primarily affected lipid packing defects.

Ergosterol and TGs also affected all investigated parameters; however, the extent of influence varied. Remarkably, the overall biophysical profile of the proposed fungal plasma membrane model closely mirrored that of natural vesicles derived from yeast lipid extracts, suggesting that this model could serve as a dependable platform for studying fungal membrane biophysics and lipid-targeting interactions.