Modeling amyloid toxic ion channels

Abstract

Non-amyloidogenic beta peptides, p3 (Aβ17-42) and Aβ11-42, resulting from α-secretase and BACE cleavage are often found in amyloid plaques. However, the biophysical properties and functional role of these non-amyloidogenic peptides are not understood. We present molecular dynamics (MD) simulations of channels consisting of the U-shaped beta-strand-turn-beta-strand peptides using available NMR-based coordinates of p3 and Aβ9-42. Our results show that non-amyloidogenic p3 and Aβ9-42 peptides form ion channel-like structures with loosely attached subunits. These channels are dynamic and are made of small peptide oligomers. The channels can conduct calcium and obtain shapes and dimensions consistent with Atomic Force Microscopy (AFM) images. All channels break into mobile subunits suggesting that membranes do not support intact β-sheet channels. We shall further present results of modeling both PG-1 and k3-β2m channels, presenting a consistent general picture of toxic beta-sheet based channels. Funded in part by DHHS #N01-CO-12400.