Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

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.