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

We consider the effect of lauric acid on the stability of various fibril‐like assemblies of Aβ peptides. For this purpose, we have performed molecular dynamics simulations of these assemblies either in complex with lauric acid or without presence of the ligand. While we do not observe a stabilizing effect on Aβ40‐fibrils, we find that addition of lauric acid strengthens the stability of fibrils built from the triple‐stranded S‐shaped Aβ42‐peptides considered to be more toxic. Or results may help to understand how the specifics of the brain‐environment modulate amyloid formation and propagation.

We consider the effect of lauric acid on the stability of various fibril-like assemblies of Aβ peptides. For this purpose, we have performed molecular dynamics simulations of these assemblies either in complex with lauric acid or without presence of the ligand. While we do not observe a stabilizing effect on Ab40-fibrils we find that addition of lauric acid strengthen the stability of fibrils built from the more toxic triple-stranded S-shaped Ab42-peptides. Or results may help to understand how specifics of the brain-environment modulate amyloid formation and propagation.

ABSTRACT:We propose a variant of the recently found S-shaped Aβ 1−42 -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. peer-reviewed)