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Hayward, Steven 
ORCID: https://orcid.org/0000-0001-6959-2604 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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Abstract
X-ray fiber diffraction experiments on Alzheimer Aβ(1–40) fibrils formed in an assembly process thought to simulate a portion of the pathophysiological process in Alzheimer's disease, 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 (MD) 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. The 12-strand structure did, however, 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 neighboring β-strip helices, resulting in a protofilament that keeps growing in both directions. Communicated by Ramaswamy H. Sarma.
| 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 |
| UEA Research Groups: | Faculty of Science > Research Groups > Computational Biology |
| Related URLs: | |
| Depositing User: | Pure Connector |
| Date Deposited: | 17 May 2018 14:32 |
| Last Modified: | 20 Apr 2023 02:32 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/67118 |
| DOI: | 10.1080/07391102.2018.1477626 |
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