Membrane-bound structure and energetics of α-synuclein

Aggregation and fibrillation of alpha-synuclein bound to membranes are believed to be involved in Parkinson's and other neurodegenerative diseases. On SDS micelles, the N-terminus of alpha-synuclein forms two curved helices linked by a short loop. However, its structure on lipid bilayers has not been experimentally resolved. Using MD simulations with an implicit membrane model we show here that, on a planar mixed membrane, the truncated a-synuclein (residues 1-95) forms a bent helix. Bending of the helix is not due to the protein sequence or membrane binding, but to collective motions of the long helix. The backbone of the helix is similar to 2.5 angstrom above the membrane surface, with some residues partially inserted in the membrane core. The helix periodicity is 11/3 (11 residues complete three full turns) as opposed to 1815 periodicity of an ideal alpha-helix, with hydrophobic residues towards the membrane, negatively charged residues towards the solvent and lysines on the polar/nonpolar interface. A series of threonines, which are characteristic for alpha-synuclein and perhaps a phosphorylation site, is also located at the hydrophobic/hydrophilic interface with their side chain often hydrogen bonded to the main-chain atom. The calculations show that the energy penalty for change in periodicity from the 1815 to 1113 on the anionic membrane is overcome by favorable solvation energy. The binding of truncated alpha-synuclein to membranes is weak. It prefers anionic membranes but it also binds marginally to a neutral membrane, via its C-terminus. Dimerization of helical monomers on the mixed membrane is energetically favorable. However, it slightly interferes with membrane binding. This might promote lateral diffusion of the protein on the membrane surface and facilitate assembly of oligomers that precede fibrillation.