Computational study of the fibril organization of polyglutamine repeats reveals a common motif identified in β-helices

The formation of fibril aggregates by long polyglutamine sequences is assumed to play a major role in neurodegenerative diseases such as Huntington. Here, we model peptides rich in glutamine, through a series of molecular dynamics simulations. Starting from a rigid nanotube-like conformation, we have obtained a new conformational template that shares structural features of a tubular helix and of a β-helix conformational organization. Our new model can be described as a super-helical arrangement of flat β-sheet segments linked by planar turns or bends. Interestingly, our comprehensive analysis of the Protein Data Bank reveals that this is a common motif in β-helices (termed β-bend), although it has not been identified so far. The motif is based on the alternation of β-sheet and helical conformation as the protein sequence is followed from the N to the C termini (β-α_R- β-polyPro-β). We further identify this motif in the ssNMR structure of the protofibril of the amyloidogenic peptide Aβ_1-40. The recurrence of the β-bend suggests a general mode of connecting long parallel β-sheet segments that would allow the growth of partially ordered fibril structures. The design allows the peptide backbone to change direction with a minimal loss of main chain hydrogen bonds. The identification of a coherent organization beyond that of the β-sheet segments in different folds rich in parallel β-sheets suggests a higher degree of ordered structure in protein fibrils, in agreement with their low solubility and dense molecular packing.