Fully Atomistic Aβ40 and Aβ42 Oligomers in Water: Observation of Porelike Conformations.

Oligomers formed by amyloid β-protein (Aβ) are central to Alzheimer's disease (AD) pathology, yet their structure remains elusive. Of the two predominant Aβ alloforms, Aβ40 and Aβ42, the latter is more strongly associated with AD. Here, we structurally characterized Aβ40 and Aβ42 monomers through pentamers which were converted from previously derived coarse-grained (DMD4B-HYDRA) simulations into all-atom conformations and subjected to explicit-solvent MD. Free energy landscapes revealed that structural differences between Aβ40 and Aβ42 conformations increase with oligomer order up to trimers. All conformations display high statistical coil and turn content (40-50%) with minor β-strand and α-helical content (<10%). Aβ40 tetramers and pentamers exhibit significantly more elongated morphologies than the respective Aβ42 conformations. Unlike the initial DMD4B-HYDRA conformations, fully atomistic Aβ40 and Aβ42 trimers, tetramers, and pentamers form water-permeable pores, whereby the tendency for pore formation sharply increased with oligomer order and is the highest for Aβ42 pentamers. Previous studies reported that Aβ oligomers form ion channels when embedded into a cellular membrane, which causes an abnormal ion flux and eventually leads to cell death. Our findings reveal an extraordinary ability of Aβ oligomers to form pores in pure water prior to their insertion into a membrane and thus provide support to the ion channel hypothesis of AD.