We report a systematic
analysis of conformational ensembles generated
from multiseed molecular dynamics simulations of all 15 known genetic
variants of Aβ<sub>42</sub>. We show that experimentally determined
variant toxicities are largely explained by random coil content of
the amyloid ensembles (correlation with smaller EC<sub>50</sub> values; <i>R</i><sup>2</sup> = 0.54, <i>p</i> = 0.01), and to
some extent the helix character (more helix-character is less toxic, <i>R</i><sup>2</sup> = 0.32, <i>p</i> = 0.07) and hydrophobic
surface (<i>R</i><sup>2</sup> = 0.37, <i>p</i> = 0.04). Our findings suggest that qualitative structural features
of the amyloids, rather than the quantitative levels, are fundamentally
related to neurodegeneration. The data provide molecular explanations
for the high toxicity of E22 variants and for the protective features
of the recently characterized A2T variant. The identified conformational
features, for example, the local helix–coil-strand transitions
of the C-terminals of the peptides, are of likely interest in the
direct targeting of amyloids by rational drug design
