Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

AO_SCPLOWBSTRACTC_SCPLOWThe aggregation of amyloid {beta}-peptides into neurotoxic oligomers is a key feature in the development of Alzheimers disease. Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity. To gain a detailed understanding of the mutual effects of amyloid-{beta} oligomers and the neuronal membrane, we carried out a total of 12 {micro}s all-atom molecular dynamics (MD) simulations of the dimerization of the full-length A{beta}42 peptide in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The conformational changes of A{beta}42 resulting from its dimerization and interactions with the neuronal membrane are compared to those occurring upon its dimerization in the aqueous phase, which is also tested by 12 {micro}s of MD simulations. We find that the interactions with the neuronal membrane decrease the order of the A{beta}42 dimer by attenuating its propensity to form a {beta}-sheet structure. The main lipid interaction partners of A{beta}42 are the surface-exposed sugar groups of the gangliosides GM1. A{beta}42 dimerization in solution, on the other hand, is characterized by a random coil to {beta}-sheet transition that seems to be on-pathway to amyloid aggregation. As the neurotoxic activity of amyloid oligomers increases with oligomer order, the results suggest that GM1 is neuroprotective against A{beta}-mediated toxicity by inhibiting the formation of ordered amyloid oligomers.