Monomeric Aβ1-40 and Aβ1-42 Peptides in Solution Adopt Very Similar Ramachandran Map Distributions That Closely Resemble Random Coil

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