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 Aβ and Aβ, two widely studied peptide fragments of Aβ implicated in Alzheimer's disease. We demonstrate that Aβ increases the aggregation rate of Aβ 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 Aβ monomers/oligomers on the surface of preformed Aβ fibrils nucleate Aβ 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.
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| http://dx.doi.org/10.1126/sciadv.aav8216 | DOI Listing |
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