Monomeric Aβ(1-40) and Aβ(1-42) Peptides in Solution Adopt Very Similar Ramachandran Map Distributions That Closely Resemble Random Coil
Authors: Julien Roche
Ad Bax
Yang Shen
Jinfa Ying
Jung Ho Lee
Journal: Biochemistry (2016)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Alzheimer's disease; amyloid peptides; aggregation; fibrillation; Aβ(1-40)
Affiliations: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892-0510, United States.

Abstract:  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 ((3)JHNHα, (3)JC'C', (3)JC'Hα, (1)JHαCα, (2)JNCα, and (1)JNCα) 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 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 Aβ(1-42), suggests that intermolecular interactions between the hydrophobic regions of the peptide dominate the aggregation process. 

Retracted: No

PubPeer comments:
null, 
null, 
 I can see this is an old thread. Without going into the details of the other papers, I might point to some work we did with the lab of Dominic Walsh and published in 2014: https: pubmed.ncbi.nlm.nih.gov 24785004 that may help shine some light? Dominic was very mindful of sample conditions and made us record NMR spectra ONLY on samples that got straight off a SEC column and only for limited time - all in order to minimize contributions from dimers or higher order assemblies. In addition, we were constrained to work at high pH (pH 8.0) and low temperature (278 K) to further avoid any self-association. This made the NMR more challenging to do, but likely was important in the analysis and for the conclusions. When it comes to assigning the structural preferences, a few words of caution; it is customary to report SSP (secondary structure propensities) by comparison to random coil chemical shifts . These are EXTREMELY sensitive to the reference set used. You can consult some reviews or papers about this. I will point out a recent paper from my own group here: https: pubmed.ncbi.nlm.nih.gov 34146207 and a more general review on the topic: https: pubmed.ncbi.nlm.nih.gov 32696364 . Keep in mind here that these are ONLY DEVIATIONS from the INTRINSIC propensities of Ramachandran space and not absolute measures. Absolute measures of structure should be derived from J-couplings, RDCs and other data. Also, remain aware of the 1 r^6 nature of the NOE versus the linear averages obtained by other methods. This may tend to give large weights to very unlikely structures. ,