The complex self-assembly processes in three dimensions of Alzheimer’s β-peptide (Aβ) amyloid protofibrils into polymorphic mature fibrils, particularly the relative protofibril orientation and packing mechanism, are poorly understood. We report here the identification and quantification of the hierarchical self-assembly details among distinct Aβ40 fibrils, particularly the winding pictures of two, three, and four individual single-stranded protofibrils into two-, three-, and four-stranded mature fibrils, respectively, via cross-sectional analysis of atomic force microscopy (AFM) images. The statistical polymer physics analysis of fibril flexibilities from AFM characterizations as well as molecular dynamics (MD) simulations reveal a ladder-like packing mechanism rather than a closed-packing manner for the interprotofibril association into Aβ40 mature fibrils. Moreover, our MD results show atomic packing polymorphism at the well-packing interfaces even within the same multistranded fibril. This work provides mechanistic insights into the polymorphic transition of single-stranded Aβ40 protofibrils into multistranded mature fibrils at the mesoscopic level, which is useful for a more comprehensive understanding of Alzheimer’s β-peptide amyloidosis.

中文翻译：

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阶梯状Aβ40单链原纤维向多链成熟纤维的分层自组装机制

阿尔茨海默氏症的β肽（Aβ）淀粉样原纤维在3个维度上形成多态成熟原纤维的复杂自组装过程，特别是相对原纤维的取向和堆积机理，了解得很少。我们在此报告了不同Aβ40原纤维之间的分层自组装细节的鉴定和量化，特别是将两个，三个和四个单独的单链原纤维分别缠绕成两，三和四链成熟纤维的缠绕图片。 ，通过原子力显微镜（AFM）图像的截面分析。通过AFM表征和分子动力学（MD）模拟对原纤维的柔韧性进行统计高分子物理分析，揭示了原纤维间缔合成Aβ40成熟原纤维的阶梯状堆积机制，而不是封闭堆积方式。此外，我们的MD结果显示，即使在相同的多链原纤维中，在紧密堆积界面处的原子堆积多态性也是如此。这项工作在介观水平上提供了从单链Aβ40原型原纤维到多链成熟原纤维多态性转变的机械洞察力，这对于更全面地了解阿尔茨海默氏症的β肽淀粉样变性是有用的。