Putative pore structure of amyloid beta and alpha synuclein in lipid bilayers.

Abstract

Many degenerative diseases are characterized by aberrant protein aggregation. One possible mechanism of toxicity is the perturbation or permeabilization of cell membranes by certain types of oligomers. However, the structure of such membrane-inserted pore-forming complexes is unknown. Here we consider putative membrane-inserted β-barrels of Amyloid β and α-synuclein and evaluate them first in an implicit membrane model and then by multi-microsecond all atom simulation. The 11 amino acid peptide sequence of Aβ25-35 is relatively hydrophobic and readily embeds into synthetic bilayers producing ion channels. We consider octameric and decameric β barrels of different topology, strand orientation, and shear. Two decameric β barrels remain stably embedded in the membrane at the conclusion of these 5-μs all atom simulations: an antiparallel barrel with K28 in the pore lumen and a parallel barrel with the K28 in the membrane interface. Examination of the α-synuclein sequence reveals two regions that could form membrane-embedded β-hairpins: 35-56 and 64-92. We find that a 35-56 barrel remains inserted but dehydrates and collapses if all His50 are neutral. If half of the His50 are doubly protonated, however, the barrel takes an oval shape but remains hydrated and open. The 64-92 barrel remains hydrated for at least 10 µs. Our results for these pore structures may carry implications for familial Parkinson's mutations.