Aβ(1–42) is the most pathogenic amyloid-β species in Alzheimer's disease (AD). The solid-state NMR–based atomic model of an Aβ(1–42) fibril elucidates the mechanism of fibril formation and propagation in AD and other amyloid diseases. Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1–42)), rather than of the more abundant Aβ(1–40), provokes the Alzheimer's disease cascade. However, structural details of misfolded Aβ(1–42) have remained elusive. Here we present the atomic model of an Aβ(1–42) amyloid fibril, from solid-state NMR (ssNMR) data. It displays triple parallel-β-sheet segments that differ from reported structures of Aβ(1–40) fibrils. Remarkably, Aβ(1–40) is incompatible with the triple-β-motif, because seeding with Aβ(1–42) fibrils does not promote conversion of monomeric Aβ(1–40) into fibrils via cross-replication. ssNMR experiments suggest that C-terminal Ala42, absent in Aβ(1–40), forms a salt bridge with Lys28 to create a self-recognition molecular switch that excludes Aβ(1–40). The results provide insight into the Aβ(1–42)-selective self-replicating amyloid-propagation machinery in early-stage Alzheimer's disease.

The long-held views on lock-and-key versus induced fit in binding arose from the notion that a protein exists in a single, most stable conformation, dictated by its sequence. However, in solution proteins exist in a range of conformations, which may be described by statistical mechanical laws and their populations follow statistical distributions. Upon binding, the equilibrium will shift in favor of the bound conformation from the ensemble of conformations around the bottom of the folding funnel. Hence here we extend the implications and the usefulness of the folding funnel concept to explain fundamental binding mechanisms.