Monomeric Aβ^1–40 and Aβ^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 Aβ1–40 and Aβ1–42 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 Aβ1–42 compared to that of Aβ1–40 are poorly understood. To explore in detail the structural propensity of the monomeric Aβ1–40 and Aβ1–42 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 Aβ1–40 and Aβ1–42 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 Aβ1–40 were used as input for the recently developed MERA Ramachandran map analysis, yielding residue-specific backbone ϕ/ψ torsion angle distributions that closely resemble random coil distributions, the absence of a significantly elevated propensity for β-conformations in the C-terminal region of the peptide, and a small but distinct propensity for αL at K28. Our results suggest that the self-association of Aβ peptides into toxic oligomers is not driven by elevated propensities of the monomeric species to adopt β-strand-like conformations. Instead, the accelerated disappearance of Aβ NMR signals in D2O over H2O, particularly pronounced for Aβ1–42, suggests that intermolecular interactions between the hydrophobic regions of the peptide dominate the aggregation process.

High-Resolution Structures of the Amyloid-β 1–42 Dimers from the Comparison of Four Atomistic Force Fields

“…19 These scalar couplings include 3 J HN–Ha , 3 J Ha–C′ , 3 J HN–C′ , and 3 J C′–C′ , which report on the phi dihedral angle, and 1 J N–C α and 2 J N–C α , which report on the ψ dihedral angle. As can be seen on Figure 10, and assuming an uncertainty of 5% in the experimental values, 17 the F99 and FOP 3 JHN-Ha constants along the sequence are very similar and clearly different from the F22 and F14 corresponding J -profiles, with the largest deviation involving the amino acid region 16–39.…”

“…12 Interestingly, on the basis of a complete set of chemical shifts and J couplings, the 34 N-terminal residues behave identically in the two monomeric species at pH 7, and the A β 40 and A β 42 ensembles resemble random coil, with the possibility of transient heterogeneous structured conformations of low probability. 19 …”

Comparison of force fields for Alzheimer's A: A case study for intrinsically disordered proteins

“…It has been suggested that a ‐hairpin in the C‐terminus of A could be the initial seed to start the aggregation process towards the ‐sheet rich amyloids . Recently, Roche et al . showed that A monomers resemble A and have no long‐range and only weak middle‐range NOE contacts and concluded that the peptides are mostly random coil.…”

Rapid α-oligomer formation mediated by the Aβ C terminus initiates an amyloid assembly pathway

“…Based on solution NMR analysis of Aβ 42 monomers that found no evidence of any residual secondary structure in this peptide14, Bax and colleagues recently proposed that early aggregation intermediates must be assembled via hydrophobically driven self-interactions of peptide segments in irregular structure. While our data on Aβ 42 concur that the first formed oligomers do not involve amyloid-like β-structure18 (Fig.…”