Models of β-Amyloid Ion Channels in the Membrane Suggest That Channel Formation in the Bilayer Is a Dynamic Process

Abstract

Here we model the Alzheimer beta-peptide ion channel with the goal of obtaining insight into the mechanism of amyloid toxicity. The models are built based on NMR data of the oligomers, with the universal U-shaped (strand-turn-strand) motif. After 30-ns simulations in the bilayer, the channel dimensions, shapes and subunit organization are in good agreement with atomic force microscopy (AFM). The models use the Abeta(17-42) pentamer NMR-based coordinates. Extension and bending of the straight oligomers lead to two channel topologies, depending on the direction of the curvature: 1), the polar/charged N-terminal beta-strand of Abeta(17-42) faces the water-filled pore, and the hydrophobic C-terminal beta-strand faces the bilayer (CNpNC; p for pore); and 2), the C-terminal beta-strand faces the solvated pore (NCpCN). In the atomistic simulations in a fully solvated DOPC lipid bilayer, the first (CNpNC) channel preserves the pore and conducts solvent; by contrast, hydrophobic collapse blocks the NCpCN channel. AFM demonstrated open pores and collapsed complexes. The final averaged CNpNC pore dimensions (outer diameter 8 nm; inner diameter approximately 2.5 nm) are in the AFM range (8-12 nm; approximately 2 nm, respectively). Further, in agreement with high-resolution AFM images, during the simulations, the channels spontaneously break into ordered subunits in the bilayer; however, we also observe that the subunits are loosely connected by partially disordered inner beta-sheet, suggesting subunit mobility in the bilayer. The cationic channel has strong selective affinity for Ca(2+), supporting experimental calcium-selective beta-amyloid channels. Membrane permeability and consequent disruption of calcium homeostasis were implicated in cellular degeneration. Consequently, the CNpNC channel topology can sign cell death, offering insight into amyloid toxicity via an ion "trap-release" transport mechanism. The observed loosely connected subunit organization suggests that amyloid channel formation in the bilayer is a dynamic, fluid process involving subunit association, dissociation, and channel rearrangements.

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

“…Consistent with earlier observations (5,25), the channel outer β-sheet, absent in the initial structure because of the larger curvature at the channel periphery, is recovered at certain regions and the channel organizes into several small subunits with or without disordered monomers in between ( Fig. 1 A and B).…”

“…In the averaged channel, the outer p3 channel diameter is ∼6.8 to 6.9 nm and the pore diameter is ∼1.7 nm. Our previous simulation for the p3 channel obtained three subunits (25), suggesting that even for the same channel (of differing size), subunit formations strongly depend on the fluidic bilayer dynamics. The p3 channel morphology is similar to the N9 channel, although the sequence lengths and detailed monomer conformations differ.…”

“…U-shaped motifs, first predicted by modeling of Aβ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (26), appear as a general feature of amyloid organization, suggesting that other U-shaped amyloid organizations may also form dynamic ion channels in the fluidic membrane (8). Because N9 and p3 have membrane-spanning segments, we modeled their 3D structures in the bilayer using the previous successful protocol (5,25). Using the two available Aβ oligomer coordinate sets (27,28), we constructed annular channels based on the U-shaped β-strand-turn-β-strand motif.…”

Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ17−42

“…This could be due to the more hydrophobic residues in the C-terminal segment compared to the N-terminal segment, which experience large deformation when they are exposed to the solvent. We also observed that Na + ions were easily attracted to the negatively charged Glu22 side chains in both NC and CN structures, consistent with our recent observations that a single-layered annular Aβ oligomer with the C-terminal facing the bilayer forms a stable toxic Ca 2+ -selective conducting channel in membrane 31 .…”

“…Looking into the cross section of the pore structures, the NC-CN pore was a straight and fat tube (Fig. 8a), which can easily be active in ion conductance 31 . We also observed that the exposed charged E22 at the N-terminus in the NC-CN annular structure was able to selectively attract Na + cations.…”