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.