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Structural Characteristics of Monomeric Aβ42 on Fibril in the Early Stage of Secondary Nucleation Process
Amyloid-β (Aβ) aggregates are believed to be one of the main causes of Alzheimer’s disease. Aβ peptides form fibrils having cross β-sheet structures mainly through primary nucleation, secondary nucleation, and elongation. In particular, self-catalyzed secondary nucleation is of great interest. Here,...
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Published in: | ACS chemical neuroscience 2020-10, Vol.11 (19), p.2989-2998 |
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Main Authors: | , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Amyloid-β (Aβ) aggregates are believed to be one of the main causes of Alzheimer’s disease. Aβ peptides form fibrils having cross β-sheet structures mainly through primary nucleation, secondary nucleation, and elongation. In particular, self-catalyzed secondary nucleation is of great interest. Here, we investigate the adsorption of Aβ42 peptides to the Aβ42 fibril to reveal a role of adsorption as a part of secondary nucleation. We performed extensive molecular dynamics simulations based on replica exchange with solute tempering 2 (REST2) to two systems: a monomeric Aβ42 in solution and a complex of an Aβ42 peptide and Aβ42 fibril. Results of our simulations show that the Aβ42 monomer is extended on the fibril. Furthermore, we find that the hairpin structure of the Aβ42 monomer decreases but the helix structure increases by adsorption to the fibril surface. These structural changes are preferable for forming fibril-like aggregates, suggesting that the fibril surface serves as a catalyst in the secondary nucleation process. In addition, the stabilization of the helix structure of the Aβ42 monomer on the fibril indicates that the strategy of a secondary nucleation inhibitor design for Aβ40 can also be used for Aβ42. |
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ISSN: | 1948-7193 1948-7193 |
DOI: | 10.1021/acschemneuro.0c00163 |