Effects of pH and Charge State on Peptide Assembly: The YVIFL Model System

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• 作者：Thanh D. Do ; Nichole E. LaPointe ; Nicholas J. Economou ; Steven K. Buratto ; Stuart C. Feinstein ; Joan-Emma Shea ; Michael T. Bowers
• 刊名：Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：September 19, 2013
• 年：2013
• 卷：117
• 期：37
• 页码：10759-10768
• 全文大小：577K
• 年卷期：v.117,no.37(September 19, 2013)
• ISSN：1520-5207

文摘

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.