title: Energy landscapes of the monomer and dimer of the Alzheimer's peptide Abeta(1-28).
abstract: The cytotoxicity of Alzheimer's disease has been linked to the self-assembly of the 4042 amino acid of the amyloid-beta (Abeta) peptide into oligomers. To understand the assembly process, it is important to characterize the very first steps of aggregation at an atomic level of detail. Here, we focus on the N-terminal fragment 1-28, known to form fibrils in vitro. Circular dichroism and NMR experiments indicate that the monomer of Abeta(1-28) is alpha-helical in a membranelike environment and random coil in aqueous solution. Using the activation-relaxation technique coupled with the OPEP coarse grained force field, we determine the structures of the monomer and of the dimer of Abeta(1-28). In agreement with experiments, we find that the monomer is predominantly random coil in character, but displays a non-negligible beta-strand probability in the N-terminal region. Dimerization impacts the structure of each chain and leads to an ensemble of intertwined conformations with little beta-strand content in the region Leu17-Ala21. All these structural characteristics are inconsistent with the amyloid fibril structure and indicate that the dimer has to undergo significant rearrangement en route to fibril formation.
authors: Département de Physique and Regroupement Québécois sur les Matériaux de Pointe, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada.
authors: Xiao
authors: X
authors: Dong
authors: Wei
authors: W
authors: Chen
authors: Normand
authors: N
authors: Mousseau
authors: Philippe
authors: P
authors: Derreumaux
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002942:Circular Dichroism; D003198:Computer Simulation; D019281:Dimerization; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008956:Models, Chemical; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012996:Solutions / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012996:Solutions; D012997:Solvents; C084358:amyloid beta-protein (1-28); D014867:Water