Out-of-Register Aβ42 Assemblies as Models for Neurotoxic Oligomers and Fibrils

ABSTRACTWe propose a variant of the recently found S-shaped Aβ1‒42-motif that is characterized by out-of-register C-terminal β-strands. We show that chains with this structure can not only form fibrils that are compatible with the NMR signals, but also barrel-shaped oligomers that resemble the ones formed by the much smaller cylindrin peptides. Running at physiological temperatures long all-atom molecular dynamics simulations with an explicit solvent, we study the stability of these constructs and show that they are plausible models for neurotoxic oligomers. Analyzing the transitions between different assemblies we suggest a mechanism for amyloid formation in Alzheimer’s disease.