Molecular insights into the surface-catalyzed secondary nucleation of amyloid-40 (A40) by the peptide fragment A16–22

Abstract

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 as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of A40 and A16–22, two widely studied peptide fragments of A42 implicated in Alzheimer’s disease. We demonstrate that A16–22 increases the aggregation rate of A40 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 A40 monomers/oligomers on the surface of preformed A16–22 fibrils nucleate A40 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.