概要：X-ray fibre diffraction experiments on Alzheimer Aβ(1-40) fibrils indicate 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. The 11-strand β-strip helix has qualities of both the β-barrel and the β-helix. It resemblance to a trans-membrane β-barrel could explain the ability of small oligomers of Aβ(1-40) to form toxic ion channels. Its β-helix-like quality means β-strip helices could join end-to-end resulting in a protofilament that keeps growing in both directions.
S.Hayward and A.Kitao, “Multi-strand β-sheet of Alzheimer Aβ(1-40) folds to β-strip helix: Implication for protofilament formation”, Journal of Biomolecular Structure and Dynamics, In Press.