Contribution from the Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB12, La Jolla, California 92037, and Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, United Kingdom.
J Am Chem Soc. 2000 Jun 7;122(22):5262-77. doi: 10.1021/ja9937831.
Deciphering the mechanism(s) of β-sheet mediated self-assembly is essential for understanding amyloid fibril formation and for the fabrication of polypeptide materials. Herein, we report a simple peptidomimetic that self-assembles into polymorphic β-sheet quaternary structures including protofilaments, filaments, fibrils, and ribbons that are reminiscent of the highly ordered structures displayed by the amyloidogenic peptides Aβ, calcitonin, and amylin. The distribution of quaternary structures can be controlled by and in some cases specified by manipulating the pH, buffer composition, and the ionic strength. The ability to control β-sheet-mediated assembly takes advantage of quaternary structure dependent pK(a) perturbations. Biophysical methods including analytical ultracentrifugation studies as well as far-UV circular dichroism and FT-IR spectroscopy demonstrate that linked secondary and quaternary structural changes mediate peptidomimetic self-assembly. Electron and atomic force microscopy reveal that peptidomimetic assembly involves numerous quaternary structural intermediates that appear to self-assemble in a convergent fashion affording quaternary structures of increasing complexity. The ability to control the assembly pathway(s) and the final quaternary structure(s) afforded should prove to be particularly useful in deciphering the quaternary structural requirements for amyloid fibril formation and for the construction of noncovalent macromolecular structures.
解析β-折叠介导的自组装机制对于理解淀粉样纤维形成以及多肽材料的制备至关重要。在此，我们报告了一种简单的肽模拟物，它可以自组装成多晶型β-折叠四级结构，包括原纤维、纤维、纤维和带状物，这些结构类似于淀粉样肽 Aβ、降钙素和胰岛淀粉样多肽所展示的高度有序结构。四级结构的分布可以通过操纵 pH 值、缓冲组成和离子强度来控制，在某些情况下可以指定。利用四级结构依赖性 pK(a) 扰动来控制β-折叠介导的组装。包括分析超速离心研究以及远紫外圆二色性和傅里叶变换红外光谱在内的生物物理方法表明，连接的二级和四级结构变化介导肽模拟物的自组装。电子和原子力显微镜揭示了肽模拟物组装涉及许多四级结构中间体，这些中间体似乎以收敛的方式自组装，从而提供越来越复杂的四级结构。控制组装途径和最终四级结构的能力对于解析淀粉样纤维形成的四级结构要求以及构建非共价大分子结构应该是非常有用的。
