title: Distinct phases of free α-synuclein--a Monte Carlo study.
abstract: The α-synuclein protein (αS), implicated in Parkinson's disease, shows conformational versatility. It aggregates into β-sheet-rich fibrils, occurs in helical membrane-bound forms, is disordered as a free monomer, and has recently been suggested to have a folded helical tetramer as its main physiological form. Here, we use implicit solvent all-atom Monte Carlo methods to explore the conformational ensemble sampled by the free αS monomer. We analyze secondary structure propensities, size, and topological properties and compare with existing experimental data. Our study suggests that free αS has two distinct phases. One phase has the expected disordered character. The other phase also shows large conformational variability. However, in this phase, the β-strand content is substantial, and the backbone fold shows statistical similarities with that in αS fibrils. Presence of this phase is consistent with data from low-temperature experiments. Conversion of disordered αS to this fibril-like form requires the crossing of a rather large apparent free-energy barrier.
authors.affiliation: Computational Biology & Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.
authors.forename: Sigurður Aegir
authors.initials: SA
authors.lastname: Jónsson
authors.forename: Sandipan
authors.initials: S
authors.lastname: Mohanty
authors.forename: Anders
authors.initials: A
authors.lastname: Irbäck
mesh_terms: D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D009010:Monte Carlo Method; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein