Department of Chemistry and Biochemistry, ‡Department of Physics and §Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California at Santa Barbara , Santa Barbara, California, 93106, United States.
J Phys Chem B. 2013 Sep 19;117(37):10759-68. doi: 10.1021/jp406066d. Epub 2013 Sep 4.
Peptide oligomerization is necessary but not sufficient for amyloid fibril formation. Here, we use a combination of experiments and simulations to understand how pH influences the aggregation properties of a small hydrophobic peptide, YVIFL, which is a mutant form of [Leu-5]-Enkephalin. Transmission electron microscopy and atomic force microscopy measurements reveal that this peptide forms small aggregates under acidic conditions (pH = 2), but that extensive fibrillization only occurs under basic conditions (pH = 9 and 11). Ion-mobility mass spectrometry identifies key oligomers in the oligomerization process, which are further characterized at an atomistic level by molecular dynamics simulations. These simulations suggest that terminal charges play a critical role in determining aggregation propensity and aggregate morphology. They also reveal the presence of steric zipper oligomers under basic conditions, a possible precursor to fibril formation. Our experiments suggest that multiple aggregation pathways can lead to YVIFL fibrils, and that cooperative and multibody interactions are key mechanistic elements in the early stages of aggregation.
肽的低聚化对于形成淀粉样纤维是必要的，但不是充分的。在这里，我们结合实验和模拟来理解 pH 值如何影响小分子疏水性肽 YVIFL 的聚集特性，该肽是 [Leu-5]-脑啡肽的一种突变形式。透射电子显微镜和原子力显微镜测量表明，该肽在酸性条件下（pH = 2）形成小聚集体，但只有在碱性条件下（pH = 9 和 11）才会发生广泛的纤维化。离子迁移质谱鉴定了低聚化过程中的关键低聚物，并通过分子动力学模拟在原子水平上进一步对其进行了表征。这些模拟表明末端电荷在决定聚集倾向和聚集形态方面起着关键作用。它们还揭示了碱性条件下存在空间拉链低聚物，这可能是纤维形成的前体。我们的实验表明，多种聚集途径可能导致 YVIFL 纤维形成，并且协同和多体相互作用是聚集早期阶段的关键机制要素。
