Abstract
Several atomic structures have now been found for micrometer-scale amyloid fibrils or elongated microcrystals using a range of methods, including NMR, electron microscopy, and X-ray crystallography, with parallel β-sheet appearing as the most common secondary structure. The etiology of amyloid disease, however, indicates nanometer-scale assemblies of only tens of peptides as significant agents of cytotoxicity and contagion. By combining solution X-ray with molecular dynamics, we show that antiparallel structure dominates at the first stages of aggregation for a specific set of peptides, being replaced by parallel at large length scales only. This divergence in structure between small and large amyloid aggregates should inform future design of molecular therapeutics against nucleation or intercellular transmission of amyloid. Calculations and an overview from the literature argue that antiparallel order should be the first appearance of structure in many or most amyloid aggregation processes, regardless of the endpoint. Exceptions to this finding should exist, depending inevitably on the sequence and on solution conditions.
Highlights
Toxic amyloid oligomers play a key role in Alzheimer’s, Parkinson’s, and other degenerative diseases [1,2,3,4], whereas functional amyloid can be a valuable and versatile material in nanotechnology and biomedicine [5,6,7]
Probing amyloid formation down to the smallest aggregates and earliest timescales, we find that antiparallel b-structures have a general thermodynamic advantage at these scales over the parallel structures, which are more commonly observed later and with larger sizes
Comparison between wide-angle X-ray scattering (WAXS) and calculated WAXS shows that a mixture of P and AP structures are probably present in the solution during the aggregation process
Summary
Toxic amyloid oligomers play a key role in Alzheimer’s, Parkinson’s, and other degenerative diseases [1,2,3,4], whereas functional amyloid can be a valuable and versatile material in nanotechnology and biomedicine [5,6,7]. Amyloids are generally polymorphic at the molecular level, and many examples exist of a given peptide or protein assembling with different morphologies [8,9], including filaments [10], nanotubes [11], helical ribbons [12,13,14], twisted ribbons [13,14], and crystals [14,15]. Amyloid aggregates formed from the same polypeptide can have different arrangements of the b-strands, which have been cataloged as a set of eight ‘‘symmetry classes’’ [16,17,18]. The arrangement of strands within each b-sheet is either parallel (P) (classes 1–4) or antiparallel (AP) (classes 5–8); the remaining discrimination between the eight classes is based on side-chain orientation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
