α-Synuclein Bound to Mitochondrial Membranes—Changes in Lipid Bilayer Structure and Mechanics

Abstract

The association between α-Synuclein and mitochondrial membranes is believed to be an important event in the neuronal degeneration that leads to Parkinson Disease (PD). In particular,α-Synuclein binding to mitochondrial membranes has recently been seen to cause organelle fragmentation and suppression of mitochondrial fusion. The partitioning of monomeric α-Synuclein in the lipid bilayer and subsequent bilayer remodeling has been previously described for simple, model lipid bilayers that lack the complexity of mitochondrial membranes. Here, we ran a series of coarse-grain molecular dynamics MARTINI simulations of α-Synuclein absorbed in either pure cardiolipin bilayers or in mixed lipid bilayers that reflect the lipid composition of inner mitochondrial membrane of rat brain mitochondria. We investigated changes in bilayer structure and variations in lipid solvation near α-synuclein. A thinning of the bilayer is observed in simulations having higher levels of added protein. Other aspects studied include α-Synuclein partition depth (investigated by potential of mean force calculations), bilayer bending rigidities and curvature as a function of protein and/or cardiolipin density.