Monomeric A?(1-40) and A?(1-42) Peptides in Solution Adopt Very Similar Ramachandran Map Distributions That Closely Resemble Random Coil.

ABSTRACT: The pathogenesis of Alzheimer's disease is characterized by the aggregation and fibrillation of amyloid peptides A?(1-40) and A?(1-42) into amyloid plaques. Despite strong potential therapeutic interest, the structural pathways associated with the conversion of monomeric A? peptides into oligomeric species remain largely unknown. In particular, the higher aggregation propensity and associated toxicity of A?(1-42) compared to that of A?(1-40) are poorly understood. To explore in detail the structural propensity of the monomeric A?(1-40) and A?(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 A?(1-40) and A?(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 ((3)JHNH?, (3)JC'C', (3)JC'H?, (1)JH?C?, (2)JNC?, and (1)JNC?) recorded for A?(1-40) were used as input for the recently developed MERA Ramachandran map analysis, yielding residue-specific backbone ?/? torsion angle distributions that closely resemble random coil distributions, the absence of a significantly elevated propensity for ?-conformations in the C-terminal region of the peptide, and a small but distinct propensity for ?L at K28. Our results suggest that the self-association of A? peptides into toxic oligomers is not driven by elevated propensities of the monomeric species to adopt ?-strand-like conformations. Instead, the accelerated disappearance of A? NMR signals in D2O over H2O, particularly pronounced for A?(1-42), suggests that intermolecular interactions between the hydrophobic regions of the peptide dominate the aggregation process.

SUBMITTER: Roche J 

PROVIDER: S-EPMC4750080 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature