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

Abstract

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.

β-barrel Oligomers as Common Intermediates of Peptides Self-Assembling into Cross-β Aggregates

“…The β-barrel structure as a model for small Aβ40/Aβ42 oligomers was also supported by recent hydrogen exchange mass spectrometry 24 and NMR studies 25 . Aβ40/Aβ42 oligomers with pore-like conformations was also observed in a recent computational study combining coarse-grained and all-atom simulations 26 . These β-barrel oligomers capable of spanning across the lipid bilayer and thus compatible to the “amyloid-pore” hypothesis of amyloid toxicity 15 – 17 have been postulated as the early aggregation intermediates exerting toxic effects on cells 11 .…”

Emergence of Barrel Motif in Amyloid-β Trimer: A Computational Study

“…In both simulations, Aβ(1–42) trimers are compact and much less structured than mature fibrils. Consistent with Voelker et al, 48 they form pores with a radius of 1.7–2.1 Å, suggesting molecules like water and Ca 2+ ions can pass through them. In simulation 1 , where the simulation began with random configurations, for the first time, we obtained trimer structures containing small β-barrels, but no barrels were found in simulation 2 .…”

“…In the latter study, pores with a radius in the range of 1.5–2.5 Å were detected in the Aβ42 trimer, but no β-barrel structure was found. The reason that β-barrels were found in our simulation but not in ref ( 48 ) is probably related to various modeling protocols. In this work, we used the all-atom model and performed REMD simulation with 72 replicas of 600 ns each.…”

“…Note that porelike conformations but not barrels were sampled in Aβ(1–40) and Aβ(1–42) oligomers obtained using MD simulation with random initial conformations. 48 …”

Amyloids: Regulators of Metal Homeostasis in the Synapse

“…AβP(1-40), as 5-8-mer oligomers, forms pore-like structures in the membranes, as revealed by 3-D computer simulations [119]. Nuclear magnetic resonance (NMR) studies show that AβP(1-42) pores are composed of tetrameric and hexameric oligomers [120]. Voelker et al demonstrated that AβP(1-40) as well as AβP(1-42) formed trimers to pentamers that could form ion channels in water [121].…”