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Abstract

Oligomeric aggregates of the amyloid-beta peptide(1-42) (Aβ42) are regarded as a primary cause of cytotoxicity related to membrane damage in Alzheimer’s disease. However, a dynamical and structural characterization of pore-forming Aβ42 oligomers at atomic detail has not been feasible. Here, we used Aβ42 oligomer structures previously determined in a membrane-mimicking environment as putative model systems to study the pore formation process in phospholipid bilayers with all-atom molecular dynamics simulations. Multiple Aβ42 oligomer sizes, conformations, and N-terminally truncated isoforms were investigated on the multi-μs time scale. We found that pore formation and ion permeation occur via edge conductivity and exclusively for β-sandwich structures that feature exposed side-by-side β-strand pairs formed by residues 9-21 of Aβ42. The extent of pore formation and ion permeation depends on the insertion depth of hydrophilic residues 13-16 (HHQK domain) and thus on subtle differences in the overall stability, orientation, and conformation of the aggregates in the membrane. Additionally, we determined that backbone carbonyl and polar side-chain atoms from the edge strands directly contribute to the coordination sphere of the permeating ions. Furthermore, point mutations that alter the number of favorable side-chain contacts correlate with the ability of the Aβ42 oligomer models to facilitate ion permeation in the bilayer center. Our findings suggest that membrane-inserted, layered β-sheet edges are a key structural motif in pore-forming Aβ42 oligomers independent of their size and play a pivotal role in aggregate-induced membrane permeabilization.