Molecular dynamics simulations reveal the importance of amyloid-beta oligomer β-sheet edge conformations in membrane permeabilization

Oligomeric aggregates of the amyloid-beta peptide(1-42) (A,642) 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 A,642 oligomers at atomic detail has not been feasible. Here, we used A,642 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 A,642 oligomer sizes, conformations, and N-terminally truncated isoforms were investigated on the multi -Ps time scale. We found that pore formation and ion permeation occur via edge conductivity and exclusively for ,6-sandwich structures that feature exposed side-by-side ,6-strand pairs formed by residues 9 to 21 of A,642. The extent of pore formation and ion permeation depends on the insertion depth of hydrophilic residues 13 to 16 (HHQK domain) and thus on subtle differ-ences 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 A,642 oligomer models to facilitate ion perme-ation in the bilayer center. Our findings suggest that membrane-inserted, layered,6-sheet edges are a key structural motif in pore-forming A,642 oligomers independent of their size and play a pivotal role in aggregate-induced membrane permeabilization.

Automated summary

Oligomeric aggregates of the amyloid-beta peptide(1-42) (Aβ42) are considered as the main cause of cytotoxicity and membrane damage in Alzheimer's disease. In this study, molecular dynamics simulations were used to investigate the pore formation process of Aβ42 oligomers in phospholipid bilayers. The results showed that pore formation and ion permeation occur through edge conductivity in specific oligomer structures featuring exposed side-by-side strand pairs formed by residues 9 to 21. The extent of pore formation and ion permeation depends on the insertion depth of hydrophilic residues 13 to 16 and subtle differences in the overall stability, orientation, and conformation of the aggregates in the membrane.