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Discrete Molecular Dynamics Study of Oligomer Formation by N-Terminally Truncated Amyloid β-Protein
Journal article   Open access   Peer reviewed

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

Derya Meral and Brigita Urbanc
Journal of molecular biology, v 425(12), pp 2260-2275
26 Jun 2013
DOI: https://doi.org/10.1016/j.jmb.2013.03.010
PMID: 23500806
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https://doi.org/10.1016/j.jmb.2013.03.010View
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Abstract

amyloid β-protein N-terminal truncation discrete molecular dynamics Alzheimer's disease structure–toxicity relationship
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. [Display omitted] ► N-terminally truncated Aβ relevant to AD studied in silico. ► Increased assembly propensity of N-terminally truncated Aβ consistent with in vitro data. ► Aβ without the first two residues formed oligomers with strongly disordered N-termini. ► Aβ without the first 10 residues formed compact oligomer conformations. ► Oligomers formed by these different Aβ isoforms predicted to have distinct toxicities.

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Web of Science research areas
Biochemistry & Molecular Biology
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