Research ArticleBIOCHEMISTRY

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

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Science Advances  21 Jun 2019:
Vol. 5, no. 6, eaav8216
DOI: 10.1126/sciadv.aav8216


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 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 preformed 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.

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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