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

In Alzheimer's disease (AD), amyloid beta-protein (A beta) self-assembles into toxic oligomers. Of the two predominant A beta alloforms, A beta(1-40) and A beta(1-42), the latter is particularly strongly linked to AD. N-terminally truncated and pyroglutamated A beta peptides were recently shown to seed A beta aggregation and contribute significantly to A beta-mediated toxicity, yet their folding and assembly were not explored computationally. Discrete molecular dynamics approach previously captured in vitro-derived distinct A beta(1-40) and A beta(1-42) oligomer size distributions and predicted that the more toxic A beta(1-42) oligomers had more flexible and solvent-exposed N-termini than A beta(1-40) oligomers. Here, we examined oligomer formation of A beta(3-40), A beta(3-42), A beta(11-40), and A beta(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 beta(3-40/42) had significantly more flexible and solvent-exposed N-termini than A beta(1-40/42) conformations. In contrast, in A beta(11-40/42) conformations, the N-termini formed more contacts and were less accessible to the solvent. The compactness of the A beta(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 beta(11-40) and A beta(11-42) oligomers might be less toxic than A beta(1-40) and A beta(1-42) oligomers and offer a plausible explanation for the experimentally observed increased toxicity of A beta(3-40) and A beta(3-42) and their pyroglutamated forms. (c) 2013 Elsevier Ltd. All rights reserved.