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Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end
Hisashi Okumura1,2, Satoru G Itoh1,2
1Institute for Molecular Science, Research Center for Computational Science, Okazaki, 444-8585, Japan.
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.
Insights
Alzheimer's disease-related amyloid fibrils exhibit distinct structural dynamics at their ends. Molecular dynamics simulations reveal asymmetric fibril growth, explaining experimental observations of unidirectional extension.
Area of Science:
- Biophysics
- Computational Biology
- Neuroscience
Background:
- Alzheimer's disease is linked to amyloid-beta (Aβ) fibrils.
- Aβ fibrils possess a cross-β structure with two β-sheets (β1 and β2).
- Understanding fibril end dynamics is crucial for elucidating amyloid extension mechanisms.
Purpose of the Study:
- To reveal the structure and fluctuation of Aβ42 and Aβ40 fibril ends.
- To investigate the molecular mechanisms underlying fibril extension.
- To reconcile simulation findings with experimental observations.
Main Methods:
- All-atom molecular dynamics (MD) simulations.
- Simulations conducted in explicit water for Aβ42 and Aβ40 fibrils.
- Analysis of structural conformations and fluctuations at fibril ends.
Main Results:
- Fibril ends exhibit distinct structures and fluctuations: 'even' ends are closed and stable, while 'odd' ends are open and dynamic.
- The 'even' end shows closer spacing of β1 and β2 sheets due to stronger β1 sheet formation.
- The 'odd' end displays greater Aβ peptide fluctuation and wider separation of β-sheets.
Conclusions:
- Asymmetric fibril end dynamics explain the observed unidirectional fibril extension in experiments.
- Molecular dynamics simulations provide insights consistent with high-speed atomic force microscopy data.
- The study clarifies the structural basis for amyloid fibril elongation in Alzheimer's disease.
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