Structural insights into amyloid-β(1-42) fibril elongation

The aggregation of the intrinsically disordered amyloid-β peptides into higher order structures called amyloid fibrils is associated with the onset and development of Alzheimer’s disease.
Here, we use molecular dynamics simulations to explore the structural rearrangement of amyloid-β(1-42) monomers during fibril elongation. Starting from the recent solid-state NMR structure of the double horseshoe amyloid-β(1-42) fibril [1,2] we employ both conventional and enhanced sampling techniques to access metastable states that are outside of the resolution of experimental techniques.
We identify the growing end of the double filament amyloid-β fibril polymorph and hypothesize on the monomer attachment/detachment mechanisms. Additionally, we inform on the fibril twist and correlate results with experimental findings.

[1] Wälti MA et al. PNAS 2016;113:E4976-E84
[3] Colvin MT et al. JACS 2016;138:9663-74