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

Abstract

The aggregation of amyloid β-peptides into neurotoxic oligomers is a key feature in the development of Alzheimer's 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-β oligomers and the neuronal membrane, we carried out a total of 12 μs all-atom molecular dynamics (MD) simulations of the dimerization of the full-length Aβ42 peptide in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The conformational changes of Aβ42 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 μs of MD simulations. We find that the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. Aβ42 dimerization in solution, on the other hand, is characterized by a random coil to β-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 Aβ-mediated toxicity by inhibiting the formation of ordered amyloid oligomers.

Disrupting Dimeric β-Amyloid by Electric Fields

“…We then use MD simulations to analyze the flexibility of the predicted structures. The top models are structurally stable in 50-ns MD runs and compare to highly populated clusters of μs scale MD simulations (published by others 15 ). Next, we use the highest-confidence prediction to test the effect of an oscillating electric field on the behavior of the Aβ peptide dimer.…”

“…Fatafta et al have sampled the conformational space of dimeric Aβ42 at a lipid bilayer that reflects the composition of neuronal membranes. 15 This sampling could be used as starting point for a simulation study in the presence of an electric field. Due to the low dielectric constant of lipid bilayers (around 3, ref 48) compared to that of water at physiological temperature (78.5), one can expect a stronger influence on the electrostatic interactions between polar groups of Aβ42.…”

“…This analysis has shown the propensity of the Aβ42 dimers to form β-strand hairpins in solution. 15 Other groups have used different techniques to predict the ensemble of conformations of the dimer. One of such approaches is the use of blockwise excursion sampling, which has yielded dimers with a secondary structure content in agreement with circular dichroism (CD) experimental data.…”

“…12−14 The most populated conformations of the Aβ42 homodimer have been recently predicted by the use of atomistic MD simulations. 15 First, an equilibrated structure of the monomer was sampled by microsecond-range MD simulations, after which two representative structures of the monomer were chosen for simulations of the dimeric system. An initial 1 μs simulation was performed, from which five subsequent 1 μs simulations were randomly restarted for a total of 6 μs sampling.…”

In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer’s Disease

“…It is important to obtain ΔG values and ligand binding modes on different Aβ1-42 conformations which are involved during its aggregation [24]. In the cell membrane, Aβ1-42 adopts an α-helix conformation; however, when it is delivered by the catalytic activity of gamma secretase (γ-secretase), it adopts structural changes to turn into β-sheet conformation passing for a random coil conformation [25]. Then, it is of utmost importance to identify compounds with more affinity for Aβ1-42 in α-helix conformation binding of the compound reaching to residues (E22 and D23) which are involved in the conformational changes.…”