Multi-strand β-sheet of Alzheimer Aβ(1-40) folds to β-strip helix: Implication for protofilament formation

Hayward, Steven and Kitao, Akio (2019) Multi-strand β-sheet of Alzheimer Aβ(1-40) folds to β-strip helix: Implication for protofilament formation. Journal of Biomolecular Structure and Dynamics, 37 (8). pp. 2143-2153. ISSN 1538-0254

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X-ray fibre diffraction experiments on Alzheimer Aβ(1-40) fibrils (Fraser et al. Biochemistry 31, 1992; Malinchik et al. Biophysical Journal, 74, 1998) indicated protofilaments with tilted β-strands rather than strands oriented perpendicular to the fibril axis as is usually interpreted from cross-β patterns. The protofilament width and tilt angle determined by these experiments were used to predict a β-strip helix model – a β-helix-like structure in which multiple identical polypeptide molecules assemble in-register to form a helical sheet structure such that the outer strands 1 and m join with a register shift t – with m = 11 and t = 22. Starting from untwisted β-sheets comprising 10, 11 and 12 strands, multiple explicit solvent Molecular Dynamics simulations were performed to determine whether the sheets form β-strip helices matching the dimensions of the experimentally measured protofilament. In the simulations, the predicted 11-strand sheets curled up to form a closed β-strip helix like structure with dimensions matching experimental values, whereas the 10- and 12-strand sheets did not form a closed helical structure. However, the 12-strand structure did show similarity to a cross-β structure determined by a solid-state NMR experiment. The 11-strand β-strip helix resembles a trans-membrane β-barrel which could explain the ability of small oligomers of Aβ(1-40) to form toxic ion channels. A further consequence of opposite sides of the 11-strand strip coming together at a register shift of 22 is end-to-end joins between neighbouring β-strip helices, resulting in a protofilament that keeps growing in both directions.

Item Type: Article
Uncontrolled Keywords: molecular dynamics simulation,cross-β,shear number,β-helix,β-barrel
Faculty \ School: Faculty of Science > School of Computing Sciences
Depositing User: Pure Connector
Date Deposited: 17 May 2018 14:32
Last Modified: 15 May 2020 00:11
DOI: 10.1080/07391102.2018.1477626

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