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.

中文翻译：

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淀粉样β（1-40）纤维中的F19-L34接触的摄动仅诱导局部结构变化，但消除细胞毒性

我们探讨了由携带Phe ₁₉到Lys ₁₉突变的突变淀粉样蛋白β（Aβ（1-40））肽形成的原纤维的结构细节，这表明该蛋白完全消除了该分子的毒性。计算机模型表明，在原纤化时，带正电的Lys ₁₉侧链从疏水原纤维内部排出。这可以通过整个下部β链的180°翻转（模型M1）或在突变位点直接附近的二级结构的局部扰动（模型M2）来解决。这伴随着M1模型中Glu ₂₂和Lys ₂₈之间的新盐桥的形成。实验上，Phe ₂₀和Leu ₃₄之间有一种新颖的接触以及残留物20-23的明显结构扰动都可以得到证实。但是，突变的原纤维没有显示出任何盐桥的形成。这表明，尽管形态上非常健壮，但Aβ（1-40）序列的局部扰动会导致中等程度的结构改变，对这些聚集体的生理重要性产生巨大影响，这可能为开发针对阿尔茨海默氏病的药物提供了替代策略。