The Unique Alzheimer’s β-Amyloid Triangular Fibril Has a Cavity along the Fibril Axis under Physiological Conditions

Abstract

Elucidating the structure of Aβ 1-40 fibrils is of interest in Alzheimer's disease research because it is required for designing therapeutics that target Aβ 1-40 fibril formation at an early stage of the disease. M35 is a crucial residue because of its potential oxidation and its strong interactions across β-strands and across β-sheets in Aβ fibrils. Experimentally, data for the three-fold symmetry structure of the Aβ 9-40 fibril suggest formation of tight hydrophobic core through M35 interactions across the fibril axis and strong I31-V39 interactions between different cross-β units. Herein, based on experimental data, we probe conformers with three-fold symmetry of the fulllength Aβ 1-40 . Our all-atom molecular dynamics simulations in explicit solvent of conformers based on the ssNMR data reproduced experimental observations of M35-M35 and I31-V39 distances. Our interpretation of the experimental data suggests that the observed ~5-7Å M35-M35 distance in the fibril three-fold symmetry structure is likely to relate to M35 interactions along the fibril axis, rather than across the fibril axis, since our measured M35-M35 distances across the fibril axis are consistently above 15Å. Consequently, we revealed that the unique Aβ 1-40 triangular structure has a large cavity along the fibril axis and that the N-termini can assist in the stabilization of the fibril by interacting with the U-turn domains or with the C-termini domains. Our findings, together with the recent cyroEM characterization of the hollow core in Aβ 1-42 fibrils, point to the relevance of a cavity in Aβ 1-40/1-42 oligomers which should be considered when targeting oligomer toxicity.

Dynamics of Amyloid β Fibrils Revealed by Solid-state NMR

“…Moreover, such low order parameters would be expected to abolish or to strongly attenuate the cross-polarization signal of these protein parts (27), which was not observed here. Perhaps the tendency of A␤ peptides to form an additional ␤-strand for amino acids 4 -7, which was also observed in some structural studies by solidstate (5) and solution (7) NMR or molecular dynamics simulation (28), can explain the absence of high molecular dynamics in this region. Second, the fact that the order parameters of the first two residues (Asp 1 and Ala 2 ) are actually higher than for Glu 3 suggests that the N terminus represents a somewhat structurally confined segment that may also be stabilized in the course of peptide aggregation.…”

On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

“…10 The average number of water molecules around each side-chain is shown in Figure 7 for both the in vivo model and the in vitro systems with three-fold symmetry. The presence of water in the central pore 22,26 observed in our molecular dynamics simulations suggests cell membrane leakage as a possible mechanism for oligomer-mediated toxicity. 17 The possibility that oligomers of Ab could be formed outside the membrane, bind to the cell surface and then span the membrane for the formation of active channels has been proposed by Shafrir et al 31 Further computational studies of Ab aggregation with three-fold symmetry in the presence of lipid membranes may help to identify which of the amyloid peptide models are stable and remain sufficiently open for ion diffusion.…”

“…2,[19][20][21] Polymorphism implies different arrangements of b-sheets in amyloid fibrils and therefore differences in the network of hydrogen bonds that determines the structural characteristics and properties of amyloids. 2,22 Previous computational studies have demonstrated that because of differences in the contribution of hydrophobic interaction and hydrogen bonds 16 oligomers with two-fold are more stable than such with the three-fold symmetry. For this reason, we have also analyzed the hydrogen bond networks observed in our models (Table I).…”

“…Periodic boundary conditions are enforced, and electrostatic interactions are calculated with the PME algorithm. 43,44 We use a time step of 2 fs. Hydrogen atoms are constrained with the LINCS 45 algorithm, while for water the Settle algorithm is used.…”

Stability of Iowa mutant and wild type Aβ-peptide aggregates

“…26 We ran several long all-atom explicit water molecular dynamic simulations in order to explain the structural and energetic differences between the parallel and antiparallel arrangement of the wild type and Iowa mutant aggregates. Our molecular dynamics simulations use a combination of the CHARMM27 force field with CMAP corrections [27][28][29] with explicit water (TIP3P), 30, 31 a common choice for exploring amyloid peptide aggregation, 32,33 as implemented in the GROMACS program version 4.6.2. 34 Hydrogen atoms are added with the pdb2gmx module of the GROMACS suite.…”