title: Comparing the folding free-energy landscapes of Abeta42 variants with different aggregation properties.
abstract: The properties of the amyloid-beta peptide that lead to aggregation associated with Alzheimer's disease are not fully understood. This study aims at identifying conformational differences among four variants of full-length Abeta42 that are known to display very different aggregation properties. By extensive all-atom Monte Carlo simulations, we find that a variety of beta-sheet structures with distinct turns are readily accessible for full-length Abeta42. In the simulations, wild type (WT) Abeta42 preferentially populates two major classes of conformations, either extended with high beta-sheet content or more compact with lower beta-sheet content. The three mutations studied alter the balance between these classes. Strong mutational effects are observed in a region centered at residues 23-26, where WT Abeta42 tends to form a turn. The aggregation-accelerating E22G mutation associated with early onset of Alzheimer's disease makes this turn region conformationally more diverse, whereas the aggregation-decelerating F20E mutation has the reverse effect, and the E22G/I31E mutation reduces the turn population. Comparing results for the four Abeta42 variants, we identify specific conformational properties of residues 23-26 that might play a key role in aggregation.
authors.affiliation: Computational Biology and Biological Physics, Lund University, Sölvegatan 14A, SE-223 62 Lund, Sweden.
authors.forename: Simon
authors.initials: S
authors.lastname: Mitternacht
authors.forename: Iskra
authors.initials: I
authors.lastname: Staneva
authors.forename: Torleif
authors.initials: T
authors.lastname: Härd
authors.forename: Anders
authors.initials: A
authors.lastname: Irbäck
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D003198:Computer Simulation; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry*; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D020033:Protein Isoforms; C075222:amyloid beta-protein (1-42)