Monomeric Aβ1–40 and Aβ1–42 Peptides in Solution Adopt Very Similar RamachandranMap Distributions That Closely Resemble Random Coil

摘要

The pathogenesis of Alzheimer’s disease is characterized by the aggregation and fibrillation of amyloid peptides Aβ^1–40 and Aβ^1–42 into amyloid plaques. Despite strong potential therapeutic interest, the structural pathways associated with the conversion of monomeric Aβ peptides into oligomeric species remain largely unknown. In particular, the higher aggregation propensity and associated toxicity of Aβ^1–42 compared to that of Aβ^1–40 are poorly understood. To explore in detail the structural propensity of the monomeric Aβ^1–40 and Aβ^1–42 peptides in solution, we recorded a large set of nuclear magnetic resonance (NMR) parameters, including chemical shifts, nuclear Overhauser effects (NOEs), and J couplings. Systematic comparisons show that at neutral pH the Aβ^1–40 and Aβ^1–42 peptides populate almost indistinguishable coil-like conformations. Nuclear Overhauser effect spectra collected at very high resolution remove assignment ambiguities and show no long-range NOE contacts. Six sets of backbone J couplings (³JHNHα, ³JC′C′, ³JC′Hα, ¹JHαCα, ²JNCα, and ¹JNCα) recorded for Aβ^1–40 were used as input for the recently developed MERA Ramachandran map analysis, yielding residue-specific backbone ϕ/ψ torsion angle distributions that closelyresemble random coil distributions, the absence of a significantlyelevated propensity for β-conformations in the C-terminal regionof the peptide, and a small but distinct propensity for αL at K28. Our results suggest that the self-association ofAβ peptides into toxic oligomers is not driven by elevated propensitiesof the monomeric species to adopt β-strand-like conformations.Instead, the accelerated disappearance of Aβ NMR signals inD2O over H2O, particularly pronounced for Aβ^1–42, suggests that intermolecular interactions betweenthe hydrophobic regions of the peptide dominate the aggregation process.