Molecular dynamics study of water channels in natural and synthetic amyloid-β fibrils

We compared all-atom explicit solvent molecular dynamics simulations of three types of Aβ(1-40) fibrils: brain-seeded fibrils (2M4J, with a threefold axial symmetry) and the other two, all-synthetic fibril polymorphs (2LMN and 2LMP, made under different fibrillization conditions). Fibril models were constructed using either a finite or an infinite number of layers made using periodic images. These studies yielded four conclusions. First, finite fibrils tend to unravel in a manner reminiscent of fibril dissolution, while infinite fibrils were more stable during simulations. Second, salt bridges in these fibrils remained stable in those fibrils that contained them initially, and those without salt bridges did not develop them over the time course of the simulations. Third, all fibrils tended to develop a "stagger" or register shift of β-strands along the fibril axis. Fourth and most importantly, the brain-seeded, 2M4J, infinite fibrils allowed bidirectional transport of water in and out of the central longitudinal core of the fibril by rapidly developing gaps at the fibril vertices. 2LMP fibrils also showed this behavior, although to a lesser extent. The diffusion of water molecules in the fibril core region involved two dynamical states: a localized state and directed diffusion in the presence of obstacles. These observations provided support for the hypothesis that Aβ fibrils could act as nanotubes. At least some Aβ oligomers resembled fibrils structurally in having parallel, in-register β-sheets and a sheet-turn-sheet motif. Thus, our findings could have implications for Aβ cytotoxicity, which may occur through the ability of oligomers to form abnormal water and ion channels in cell membranes.