Abstract
We explored structural details of fibrils formed by a mutated amyloid β (Aβ(1-40)) peptide carrying a Phe19 to Lys19 mutation, which was shown to completely abolish the toxicity of the molecule. Computer models suggest that the positively charged Lys19 side chain is expelled from the hydrophobic fibril interior upon fibrillation. This can be accommodated by either a 180° flip of the entire lower β-strand (model M1) or local perturbations of the secondary structure in the direct vicinity of the mutated site (model M2). This is accompanied by the formation of a new salt bridge between Glu22 and Lys28 in model M1. Experimentally, a novel contact between Phe20 and Leu34 as well as the significant structural perturbation of residues 20-23 could be confirmed. However, the mutated fibrils do not show the formation of any salt bridges. This demonstrates that although morphologically very robust, local perturbations of the Aβ(1-40) sequence lead to moderate structural alterations with tremendous impact on the physiological importance of these aggregates, which may suggest alternative strategies for the development of a remedy against Alzheimer's disease.
Published Version
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