Abstract
Aβ amyloid fibrils, which are related to Alzheimer’s disease, have a cross-β structure consisting of two β-sheets: β1 and β2. The Aβ peptides are thought to be serially arranged in the same molecular conformation along the fibril axis. However, to understand the amyloid extension mechanism, we must understand the amyloid fibril structure and fluctuation at the fibril end, which has not been revealed to date. Here, we reveal these features by all-atom molecular dynamics (MD) simulations of Aβ42 and Aβ40 fibrils in explicit water. The structure and fluctuation were observed to differ between the two ends. At the even end, the Aβ peptide always took a closed form wherein β1 and β2 were closely spaced. The Aβ peptide fluctuated more at the odd end and took an open form wherein the two β-sheets were well separated. The differences are attributed to the stronger β-sheet formation by the β1 exposed at the even end than the β2 exposed at the odd end. Along with the small fluctuations at the even end, these results explain why the fibril extends from one end only, as observed in experiments. Our MD results agree well with recent observations by high-speed atomic force microscopy.
Highlights
Amyloid fibrils, insoluble fibrous aggregates of misfolded proteins or peptides, are associated with approximately 40 human neurodegenerative diseases[1,2,3,4]
We revealed the structural and fluctuational differences between the even and odd ends of the Aβ fibrils in all-atom molecular dynamics (MD) simulations
The conformational flexibility of the odd end is attributed to the exposed β2, which forms weak hydrogen bonds
Summary
Insoluble fibrous aggregates of misfolded proteins or peptides, are associated with approximately 40 human neurodegenerative diseases[1,2,3,4]. To understand the molecular mechanism underlying amyloid fibril elongation, we must reveal the atomic structure of the fibril ends. This knowledge is important for drug design as blocking the fibril ends would prevent fibril elongation. The fibril end forms the interface between the amyloid fibril and solution and may generally adopt a different molecular structure and character from the peptides in the bulk region. The structural and fluctuational differences between the odd and even ends have not been investigated To reveal these differences, the present study conducts MD simulations on Aβ amyloid fibrils composed of 20 Aβ42 peptides and 20 Aβ40 peptides in explicit water. We predict the Aβ molecular structures at the fibril ends, which have not been experimentally determined, from a surface-science perspective
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
