title: Early oligomerization stages for the non-amyloid component of α-synuclein amyloid.
abstract: In recent years, much effort has focused on the early stages of aggregation and the formation of amyloid oligomers. Aggregation processes for these proteins are complex and their non-equilibrium nature makes any experimental study very difficult. Under these conditions, simulations provide a useful alternative for understanding the dynamics of the early stages of oligomerization. Here, we focus on the non-Aβ amyloid component (NAC) of the monomer, dimer, and trimer of α-synuclein, an important 35-residue sequence involved in the aggregation and fibrillation of this protein associated with Parkinson's disease. Using Hamiltonian and temperature replica exchange molecular dynamics simulations combined with the coarse grained Optimized Potential for Efficient peptide structure Prediction potential, we identify the role of the various regions and the secondary structures for the onset of oligomerization. For this sequence, we clearly observe the passage from α-helix to β-sheet, a characteristic transition of amyloid proteins. More precisely, we find that the NAC monomer is highly structured with two α-helical regions, between residues 2-13 and 19-25. As the dimer and trimer form, β-sheet structures between residues 2-14 and 26-34 appear and rapidly structure the system. The resulting conformations are much more structured than similar dimers and trimers of β-amyloid and amylin proteins and yet display a strong polymorphism at these early stages of aggregation. In addition to its inherent experimental interest, comparison with other sequences shows that NAC could be a very useful numerical model for understanding the onset of aggregation.
authors.affiliation: Département de Physique and Groupe de recherche sur les protéines membranaires (GEPROM), Université de Montréal, C.P. 6128, succursale Centre-ville, Montréal, Québec H3C 3J7, Canada.
authors.forename: Cindie
authors.initials: C
authors.lastname: Eugene
authors.affiliation: Département de Physique and Groupe de recherche sur les protéines membranaires (GEPROM), Université de Montréal, C.P. 6128, succursale Centre-ville, Montréal, Québec H3C 3J7, Canada.
authors.forename: Rozita
authors.initials: R
authors.lastname: Laghaei
authors.affiliation: Department of Chemistry, University of Pittsburgh, 319 Eberly Hall, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Normand
authors.initials: N
authors.lastname: Mousseau
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D066329:Protein Aggregates; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000682:Amyloid; D066329:Protein Aggregates; D051844:alpha-Synuclein