Transmembrane β-Barrel Topology Model for Alzheimer's β-Amyloid (Aβ) Ion Channels

Abstract

We modeled Alzheimer's amyloidβ (Aβ) ion channel in a β-barrel-like organization embedded in a lipid bilayer using explicit molecular dynamics (MD) simulations. The β-barrel motif is common in transmembrane toxin pores, typically consisting of a monomeric chain that forms a circular β-sheet with antiparallel β-strands stabilized by the connecting loops. In our simulations, Aβ barrels consist of multimeric chains forming two β-sheets arranged by parallel β-strands, where the strands of each monomer are connected by a turn. Our conceptual designs of Aβ barrels employ the U-shaped β-strand-turn-β-strand peptides using currently available NMR-based coordinates for Aβ17-42 (known as p3) and Aβ9-42 (called N9) peptides. Recently, it has been demonstrated that the N-terminal truncated Aβ peptides are capable of forming ion-permeable channels and their morphologies are consistent with atomic force microscopy (AFM) images of full-length Aβ1-42 channels. Since no experimental coordinates for the membrane embedded structure of full-length Aβ1-42 are currently available, we generated two U-shaped Aβ1-42 peptides from both p3 and N9 peptides through an extension of their N-termini by adapting the NMR-based coordinates of solution structure of Aβ1-16. In good agreement with AFM images and previous modeling, all Aβ barrels, including p3, N9, and Aβ1-42 barrels break into heterogeneous, loosely-associated mobile β-sheet subunits, verifying that membranes do not support intact β-sheet conformations. The subunits appear mobile and allow unregulated, hence toxic, ion flux. In the Aβ channels, the presence of β-barrel-like conformation and the formation of ion-permeable barrels with hybrid monomer conformation suggest that Aβ barrel is a populated polymorphic variant of Aβ channels. Funded by NCI Contract HHSN261200800001E (RN) and NIH (NIA) extramural program (RL).