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Discrete Molecular Dynamics Study of Oligomer Formation by N-Terminally Truncated Amyloid β-Protein

Meral, Derya, Urbanc, Brigita
Journal of Molecular Biology 2013 v.425 pp. 2260-2275
Alzheimer disease, amino acids, amyloid, hydrophobicity, molecular dynamics, peptides, toxicity
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.