Familial Alzheimer’s Disease Osaka Mutant (ΔE22) β-Barrels Suggest an Explanation for the Different Aβ_1–40/42 Preferred Conformational States Observed by Experiment

Abstract

An unusual ΔE693 mutation in the amyloid precursor protein (APP) producing a β-amyloid (Aβ) peptide lacking glutamic acid at position 22 (Glu22) was recently discovered, and dabbed the Osaka mutant (ΔE22). Previously, several point mutations in the Aβ peptide involving Glu22 substitutions were identified and implicated in the early onset of familial Alzheimer’s disease (FAD). Despite the absence of Glu22, the Osaka mutant is also associated with FAD, showing a recessive inheritance in families affected by the disease. To see whether this aggregation-prone Aβ mutant could directly relate to the Aβ ion channel-mediated mechanism as observed for the wild type (WT) Aβ peptide in AD pathology, we modeled Osaka mutant β-barrels in a lipid bilayer. Using molecular dynamics (MD) simulations, two conformer ΔE22 barrels with the U-shaped monomer conformation derived from NMR-based WT Aβ fibrils were simulated in explicit lipid environment. Here, we show that the ΔE22 barrels obtain the lipid-relaxed β-sheet channel topology, indistinguishable from the WT Aβ1–42 barrels, as do the outer and pore dimensions of octadecameric (18-mer) ΔE22 barrels. Although the ΔE22 barrels lose the cationic binding site in the pore which is normally provided by the negatively charged Glu22 side-chains, the mutant pores gain a new cationic binding site by Glu11 at the lower bilayer leaflet, and exhibit ion fluctuations similar to the WT barrels. Of particular interest, this deletion mutant suggests that toxic WT Aβ1–42 would preferentially adopt a less C-terminal turn similar to that observed for Aβ17–42, and explains why the solid state NMR data for Aβ1–40 point to a more C-terminal turn conformation. The observed ΔE22 barrels conformational preferences also suggest an explanation for the lower neurotoxicity in rat primary neurons as compared to WT Aβ1–42.

Amyloid β Ion Channels in a Membrane Comprising Brain Total Lipid Extracts

“…Anionic DOPS/POPE (1:2 molar ratio) lipid membranes were used to simulate the pore structure of Aβ 1–42 . We modeled Aβ 1–42 pores in a β-barrel topology using two Aβ 1–42 conformers with the β-strand-turnEβ-strand motif in a similar manner as we reported in previous computational studies 22,45,46 . Explicit MD simulations on Aβ 1–42 barrels embedded in the DOPS/POPE membrane provided fully relaxed pore conformations in the lipid environment 45 .…”

Mechanisms of Membrane Binding of Small GTPase K-Ras4B Farnesylated Hypervariable Region

“…The lipid bilayers were generated using the bilayer building protocol as described in our previous publications (91,92). At both bilayer leaflets, pseudo spheres interacting through the van der Waals (vdW) force field were generated (43,44).…”

Computational Methods for Structural and Functional Studies of Alzheimer’s Amyloid Ion Channels

“…Unlike point substitution, Osaka mutant (ΔE22) eliminates residue Glu22 from the pore-lining β-strand [40]. As a result, pore-lining residues 10-21 for both conformers flip their side chains, while the other domains remain intact (Fig.…”

“…Probability distribution functions, P, for ions representing ionic permeation as a function of the distance along the pore center axis can be calculated over the simulations. Peaks in the distribution curve represent the cationic binding sites [30,34,40,45,59]. …”

“…To observe ion fluctuation across the pore, the change in total charge, ΔQ (C/ns), in the pore as a function of the simulation time can be calculated. In the calculations, different pore lengths with different cutoffs along the pore axis are used [36,37,40,42].…”