Energy landscapes of the monomer and dimer of the Alzheimer's peptide AΒ (1-28)

Abstract

The cytoxicity of Alzheimer's disease has been linked to the self-assembly of the 4042 amino acid of the amyloid- Β (AΒ) 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 AΒ (1-28) is α -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 AΒ (1-28). In agreement with experiments, we find that the monomer is predominantly random coil in character, but displays a non-negligible Β -strand probability in the N-terminal region. Dimerization impacts the structure of each chain and leads to an ensemble of intertwined conformations with little Β -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. © 2008 American Institute of Physics.