Chiral Selectivity of Secondary Nucleation in Amyloid Fibril Propagation

Chirality is a fundamental feature of asymmetric molecules and of critical importance for intermolecular interactions. The growth of amyloid fibrils displays a strong enantioselectivity, which is manifested as elongation through the addition of monomers of the same, but not opposite, chirality as the parent aggregate. Here we ask whether also secondary nucleation on the surface of amyloid fibrils, of relevance for toxicity, is governed by the chirality of the nucleating monomers. We use short amyloid peptides (Aβ20-34 and IAPP20-29) with all residues as L- or all D-enantiomer in self and cross-seeding experiments with low enough seed concentration that any acceleration of fibril formation is dominated by secondary nucleation. We find a strong enantio-specificity of this auto-catalytic process with secondary nucleation being observed in the self-seeding experiments only. The results highlight a role of secondary nucleation in strain propagation.