Distinct phases of free α-synuclein - A Monte Carlo study.

Summary, in English

The α-synuclein protein (αS), implicated in Parkinson's disease (PD), 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 (MC) 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. Proteins 2012. © 2012 Wiley Periodicals, Inc.

• Author: Sigurdur Jonsson; Sandipan Mohanty; Anders Irbäck
• Department/s: Computational Biology and Biological Physics - Has been reorganised; MultiPark: Multidisciplinary research on neurodegenerative diseases
• Publishing year: 2012
• Language: English
• Pages: 2169-2177
• Publication/Series: Proteins
• Volume: 80
• Issue: 9
• Links: http://dx.doi.org/10.1002/prot.24107
• Document type: Journal article
• Publisher: Wiley-Liss Inc.
• Topic: Biophysics
• Keywords: amyloid; conformational heterogeneity; protein aggregation; protein folding; protein misfolding
• Status: Published
• ISBN/ISSN/Other: ISSN: 0887-3585