Abstract
We modeled Alzheimer's Aβ ion channel in a β-barrel structure embedded in the lipid bilayer using molecular dynamics (MD) simulations. The β-barrel is characterized by the inclination angle of the β-strands with respect to the pore axis. Our Aβ barrels have two β-strand layers, and each layer has 16 or 20 β-strands that are tilted by ∼37° relative to the membrane normal. In the Aβ barrel simulations, we employed the U-shaped β-strand-turn-β-strand peptides using currently available NMR-based coordinates of non-amyloidogenic p3 (Aβ17-42) and Aβ9-42 peptides. The non-amyloidogenic Aβs resulting from α-secretase and BACE cleavage are often found in amyloid plaques, but the biophysical properties and functional role of these non-amyloidogenic peptides are not understood. In good agreement with previously modeled Aβ ion channels that aligned the β-strands parallel to the pore axis, all Aβ barrels break into loosely-associated mobile β-sheet subunits, verifying that membranes do not support intact β-sheet conformations. We obtain ion-permeable pore-like Aβ barrels whose subunit morphologies and shapes are consistent with AFM images, suggesting that the Aβ barrels are polymorphic conformations of Aβ ion channels in the membrane. The emerging picture from our large-scale simulations is that toxic ion channels formed by β-sheets spontaneously break into loosely-interacting dynamic units which associate and dissociate leading to toxic ionic flux. Funded by NCI Contract HHSN261200800001E (RN) and NIH (NIA) extramural program (RL).
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