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Membrane‐bound structure and energetics of α‐synuclein
Author(s) -
Mihajlovic Maja,
Lazaridis Themis
Publication year - 2008
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21558
Subject(s) - membrane , chemistry , helix (gastropod) , crystallography , alpha synuclein , molecular dynamics , lipid bilayer , biophysics , side chain , hydrogen bond , protein structure , alpha helix , solvation , stereochemistry , solvent , molecule , biochemistry , computational chemistry , circular dichroism , biology , medicine , ecology , disease , organic chemistry , pathology , snail , parkinson's disease , polymer
Abstract Aggregation and fibrillation of α‐synuclein bound to membranes are believed to be involved in Parkinson's and other neurodegenerative diseases. On SDS micelles, the N‐terminus of α‐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 α‐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 ∼2.5 Å 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 18/5 periodicity of an ideal α‐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 α‐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 18/5 to 11/3 on the anionic membrane is overcome by favorable solvation energy. The binding of truncated α‐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. Proteins 2008. © 2007 Wiley‐Liss, Inc.