Modeling Alzheimer's Ion Channel Structures in Lipid Bilayers Formed by D- and L-Enantiomers of Beta-Amyloid (1-42) Peptide

Abstract

We modeled Alzheimer's Aβ1-42 ion channel embedded in a lipid bilayer using explicit molecular dynamics (MD) simulations. The Aβ channel with the β-barrel motif consists of multimeric chains of Aβ1-42 peptide. Two Aβ isomers, entirely composed of all D- or L-amino acids, were used to construct the Aβ barrels. In addition, both isomer barrels contain two U-shaped Aβ1-42 conformers: with a turn at Ser26-Ile31 (conformer 1) and at Asp23-Gly29 (conformer 2). In our simulations, regardless of the D- and L-amino acid chirality, both Aβ conformers form β-barrel-like channels, consistent with previous modeling of Aβ17-42 (p3) and Aβ9-42 (N9) barrels. In good agreement with atomic force microscopy (AFM) images, both D- and L-Aβ1-42 barrels break into heterogeneous, loosely-associated mobile β-sheet subunits. Further, we observed similar physicochemical predicted behaviors of the all D-amino acids enantiomer of Aβ1-42 compared to the naturally occurring all L-amino acids. Both isomer barrels obtained indistinguishable maximal conductances for ions interacting with channel pore, which are also in the range of the experimental values using planar lipid bilayer (PLB) electrophysiological recordings. It has been debated that Aβ-mediated toxicity occurs via either direct membrane permeation with a mechanism consistent with channel formation or stereospecific Aβ ligand-receptor interactions. We show that the D-enantiomer Aβ peptide can form ion channels and directly lead to toxic, amyloid-mediated effects, supporting that Aβ-toxicity is mediated through a receptor-independent, non-stereo selective mechanism. Funded by NCI Contract HHSN261200800001E (RN) and NIH (National Institute on Aging AG028709) extramural program (RL).