BPS2026 – Membrane curvature and phase cooperatively modulate α-synuclein binding through defect abundance

α-Synuclein is an intrinsically disordered protein that binds to the synaptic terminals of neurons, allowing for the proper release of neurotransmitters. However, excessive α-synuclein binding causes aggregation and has been implicated in Parkinson's disease. Lipid packing defects, where acyl tails are exposed to solvent, are suggested to mediate α-synuclein binding. Prior experiments using small unilamellar vesicles (SUVs) have shown that α-synuclein has a higher binding to SUVs containing DPPC (saturated) than DOPC (unsaturated) lipids. The difference in the saturation of these lipids influences the phase of the SUVs, with DPPC forming a gel-phase and DOPC forming a liquid-phase at room temperature. Experiments revealed higher binding of α-synuclein to SUVs containing DPPC over DOPC suggesting that gel-phase vesicles contain more defects than those in the liquid-phase. These findings are counterintuitive, as membranes in the liquid phase are expected to exhibit more packing defects from their disorganized nature. We hypothesize that this discrepancy arises because gel-phase vesicles can adopt polygonal geometries in which the membrane buckles, forming “vertices” where there is a local concentration of defects. To address this, we employ coarse-grained molecular dynamics simulations of gel and liquid phase membranes with the Martini 3 force field. We systematically vary the lipid compositions and the extent of buckling of the membranes and characterize the size and distribution of lipid packing defects. We find that buckled gel phase membranes have increased defects compared to membranes in liquid phase, with enrichment at the vertices of polygon-shaped gel-phase membranes. This work provides biophysical insights into the role of lipid compositions and membrane properties that might influence α-synuclein binding.