Discrete molecular dynamics study of oligomer formation by N-terminally truncated amyloid β-protein.

In Alzheimer's disease (AD), amyloid β-protein (Aβ) self-assembles into toxic oligomers. Of the two predominant Aβ alloforms, Aβ1-40 and Aβ1-42, the latter is particularly strongly linked to AD. N-terminally truncated and pyroglutamated Aβ peptides were recently shown to seed Aβ aggregation and contribute significantly to Aβ-mediated toxicity, yet their folding and assembly were not explored computationally. Discrete molecular dynamics approach previously captured in vitro-derived distinct Aβ1-40 and Aβ1-42 oligomer size distributions and predicted that the more toxic Aβ1-42 oligomers had more flexible and solvent-exposed N-termini than Aβ1-40 oligomers. Here, we examined oligomer formation of Aβ3-40, Aβ3-42, Aβ11-40, and Aβ11-42 by the discrete molecular dynamics approach. The four N-terminally truncated peptides showed increased oligomerization propensity relative to the full-length peptides, consistent with in vitro findings. Conformations formed by Aβ3-40/42 had significantly more flexible and solvent-exposed N-termini than Aβ1-40/42 conformations. In contrast, in Aβ11-40/42 conformations, the N-termini formed more contacts and were less accessible to the solvent. The compactness of the Aβ11-40/42 conformations was in part facilitated by Val12. Two single amino acid substitutions that reduced and abolished hydrophobicity at position 12, respectively, resulted in a proportionally increased structural variability. Our results suggest that Aβ11-40 and Aβ11-42 oligomers might be less toxic than Aβ1-40 and Aβ1-42 oligomers and offer a plausible explanation for the experimentally observed increased toxicity of Aβ3-40 and Aβ3-42 and their pyroglutamated forms.