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

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

Keywords:

• Molecular dynamics simulation
• cross-β
• shear number
• β-helix
• β-barrel

Acknowledgements

The computations were partly performed using the supercomputers at the RCCS, The National Institute of Natural Science, and ISSP, The University of Tokyo. This research also used computational resources of the K computer and other computers of the HPCI system provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project (Project ID: hp140031, hp150049, hp150270, hp160207, and hp170254).

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by MEXT/JSPS KAKENHI (Nos. 25104002 and 15H04357) to A.K. and by MEXT as “Priority Issue on Post-K Computer” (Building Innovative Drug Discovery Infrastructure through Functional Control of Biomolecular Systems) to A.K.