Stability of Aβ11-40 Trimers with Parallel and Antiparallel β-Sheet Organizations in a Membrane-Mimicking Environment by Replica Exchange Molecular Dynamics Simulation.

The aggregation of the amyloid (Aβ) peptide of 39-43 amino acids into plaques is observed in the brain of Alzheimer's disease (AD) patients, but the mechanisms underlying the neurotoxicity of Aβ oligomers are still elusive. One suggested initial mechanism is related to the implications of amyloid membrane interactions, but characterization of these assemblies is challenging by experimental means. In this study, we have explored the stability of a trimer of Aβ11-40 in parallel and antiparallel β-sheet structures for the wild-type sequence and its F20W mutant in a dipalmitoylphosphatidylcholine membrane using atomistic replica exchange molecular dynamic simulations. We show that both the U-shape organization and the assembly of β-hairpins are maintained in the membrane and are resistant to the mutation F20W. In contrast the models are destabilized by the F19P mutation. Overall, our results indicate that these two assemblies represent minimal seeds or nuclei for the formation of either amyloid fibrils, a variety of β-barrel pores, or various aggregates for many Aβ sequences in a membrane-mimicking environment.