Molecular insights into the surface-catalyzed secondary nucleation of amyloid-β₄₀ (Aβ₄₀) by the peptide fragment Aβ₁₆-₂₂

Understanding the structural mechanism by which proteins and peptides aggregate is crucial given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge given assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of Aβ40 and Aβ16-22, two widely studied peptide fragments of Aβ42 implicated in Alzheimer’s disease. We demonstrate that Aβ16-22 increases the aggregation rate of Aβ40 through a surface catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between Aβ40 monomers/oligomers on the surface of pre-formed Aβ16-22 fibrils nucleate Aβ40 amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly.