Dissecting the assembly of Aβ16-22 amyloid peptides into antiparallel β sheets

Multiple long molecular dynamics simulations are used to probe the oligomerization mechanism of Abeta(16-22) (KLVFFAE) peptides. The peptides, in the monomeric form, adopt either compact random-coil or extended beta strand-like structures. The assembly of the low-energy oligomers, in which the peptides form antiparallel beta sheets, occurs by multiple pathways with the formation of an obligatory alpha-helical intermediate. This observation and the experimental results on fibrillogenesis of Abeta(1-40) and Abeta(1-42) peptides suggest that the assembly mechanism (random coil --> alpha helix --> beta strand) is universal for this class of peptides. In Abeta(16-22) oligomers both interpeptide hydrophobic and electrostatic interactions are critical in the formation of the antiparallel beta sheet structure. Mutations of either hydrophobic or charged residues destabilize the oligomer, which implies that the 16-22 fragments of Arctic (E22G), Dutch (E22Q), and Italian (E22K) mutants are unlikely to form ordered fibrils.