Monomeric Aβ<sup>1–40</sup> and Aβ<sup>1–42</sup> Peptides in Solution Adopt Very Similar Ramachandran
Map Distributions That Closely Resemble Random Coil
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Abstract
The
pathogenesis of Alzheimer’s disease is characterized
by the aggregation and fibrillation of amyloid peptides Aβ<sup>1–40</sup> and Aβ<sup>1–42</sup> 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<sup>1–42</sup> compared to that of Aβ<sup>1–40</sup> are poorly understood. To explore in detail the structural propensity
of the monomeric Aβ<sup>1–40</sup> and Aβ<sup>1–42</sup> peptides in solution, we recorded a large set of nuclear magnetic
resonance (NMR) parameters, including chemical shifts, nuclear Overhauser
effects (NOEs), and <i>J</i> couplings. Systematic comparisons
show that at neutral pH the Aβ<sup>1–40</sup> and Aβ<sup>1–42</sup> 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 <i>J</i> couplings (<sup>3</sup><i>J</i><sub>HNHα</sub>, <sup>3</sup><i>J</i><sub>C′C′</sub>, <sup>3</sup><i>J</i><sub>C′Hα</sub>, <sup>1</sup><i>J</i><sub>HαCα</sub>, <sup>2</sup><i>J</i><sub>NCα</sub>, and <sup>1</sup><i>J</i><sub>NCα</sub>) recorded
for Aβ<sup>1–40</sup> 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 α<sub>L</sub> 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
D<sub>2</sub>O over H<sub>2</sub>O, particularly pronounced for Aβ<sup>1–42</sup>, suggests that intermolecular interactions between
the hydrophobic regions of the peptide dominate the aggregation process
