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

ABSTRACT: In Alzheimer's disease (AD), amyloid ?-protein (A?) self-assembles into toxic oligomers. Of the two predominant A? alloforms, A?1-40 and A?1-42, the latter is particularly strongly linked to AD. N-terminally truncated and pyroglutamated A? peptides were recently shown to seed A? aggregation and contribute significantly to A?-mediated toxicity, yet their folding and assembly were not explored computationally. Discrete molecular dynamics approach previously captured in vitro-derived distinct A?1-40 and A?1-42 oligomer size distributions and predicted that the more toxic A?1-42 oligomers had more flexible and solvent-exposed N-termini than A?1-40 oligomers. Here, we examined oligomer formation of A?3-40, A?3-42, A?11-40, and A?11-42 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 A?3-40/42 had significantly more flexible and solvent-exposed N-termini than A?1-40/42 conformations. In contrast, in A?11-40/42 conformations, the N-termini formed more contacts and were less accessible to the solvent. The compactness of the A?11-40/42 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 A?11-40 and A?11-42 oligomers might be less toxic than A?1-40 and A?1-42 oligomers and offer a plausible explanation for the experimentally observed increased toxicity of A?3-40 and A?3-42 and their pyroglutamated forms.

SUBMITTER: Meral D 

PROVIDER: S-EPMC3665754 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature