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Title: Molecular insights into the surface-catalyzed secondary nucleation of amyloid-β 40 (Aβ 40 ) by the peptide fragment Aβ 16–22
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 as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of Aβ 40 and Aβ 16–22 , two widely studied peptide fragments of Aβ 42 implicated in Alzheimer’s disease. We demonstrate that Aβ 16–22 increases the aggregation rate of Aβ 40 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 40 monomers/oligomers on the surface of preformed Aβ 16–22 fibrils nucleate Aβ 40 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.  more » « less
Award ID(s):
1743432
NSF-PAR ID:
10108179
Author(s) / Creator(s):
; ; ; ; ; ;
Date Published:
Journal Name:
Science Advances
Volume:
5
Issue:
6
ISSN:
2375-2548
Page Range / eLocation ID:
eaav8216
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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