(757l) Coarse-Grained Simulations of Alpha-Synuclein Adsorption to Lipid Membranes

Shen, Z., University of Wisconsin-Madison
Van Lehn, R. C., University of Wisconsin-Madison
Murphy, R. M., University of Wisconsin-Madison
Hoover, B., University of Wisconsin
Membrane-bound proteins play an important role in regulating local membrane curvature, global remodeling, and the material properties of membranes. Alpha-synuclein (aSyn) is a protein mainly found in the presynaptic termini of neurons and is closely associated with Parkinson’s disease. The interaction of aSynwith the cellular membrane is believed to be critical to its native function and possibly to its pathogenic aggregation in Parkinson’s disease. While aSyn adsorption has been previously shown to induce membrane remodeling, the effect of lipid composition on membrane remodeling is unknown. In this study, we use coarse-grained molecular dynamics simulations to study the effect of aSyn adsorption on single-component anionic lipid bilayers with varying lipid tail saturation and length.

We first examine the asymmetric adsorption ofan aSyn monomer to the upper leaflet of planar bilayers. We find that lipid composition affects the local membrane curvature generated by aSyn binding, which changes sign depending on the lipid tail characteristics. To account for the mismatch between two bilayer leaflets caused by aSyn adsorption, we also study the adsorption of monomeric aSyn to the upper leaflet of lipid ribbons, which are lipid bilayers for which all dimensions are bound by solution. We find that aSyn adsorption triggers vesicle formation in all cases with the aSyn localized to either the vesicle interior or exterior depending on the local induced curvature. We then further study the adsorption of higher concentrations of aSyn to the outer leaflet of small vesicles to relate vesicle remodeling to induced membrane curvature. We find that vesicles formed from lipids that exhibit negative curvature upon aSyn binding deform significantly in the presence of high aSyn concentrations. These findings are consistent with TEM observations of tubulation for only select lipid species. In summary, our work suggests that aSyn either promotes or destabilizes the intrinsic curvature of the vesicle depending on lipid tail structure, providing new insights into the effect of aSyn interactions on lipid membranes.