Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, USA.
J Phys Chem B. 2013 Feb 14;117(6):1770-9. doi: 10.1021/jp306386p. Epub 2013 Jan 31.
We have probed the structures and aggregation propensities of chirally substituted [Ala(2)]-Leu-Enkephalin peptides (i.e., Leu-Enkephalin G2A) with a combination of ion-mobility spectrometry/mass spectrometry and techniques of computational chemistry. Our IMS/MS data reveal a strong correlation between the propensity to form peptide dimers and the subsequent aggregation propensity. This correlation indicates that the dimerization process is fundamental to the overall self-assembly process. Our computational data correlate a conformational conversion during the peptide association process with a reduced experimental dimer formation and subsequent aggregation propensity. Furthermore, our analysis indicates that monomer activation does not precede peptide association and thus suggests that the entire-refolding or gain-in-interaction models are more realistic accounts of the peptide self-assembly process than the monomer-conversion model. In sum, our results suggest that conformational transitions of early peptide oligomers represent bottlenecks of the peptide self-assembly process and thus highlight the importance of structurally characterizing this reaction during amyloid formation.
我们结合离子迁移谱/质谱联用技术和计算化学技术，研究了手性取代的[Ala(2)]-Leu-脑啡肽（即 Leu-脑啡肽 G2A）的结构和聚集倾向。我们的 IMS/MS 数据表明，形成肽二聚体的倾向与随后的聚集倾向之间存在很强的相关性。这种相关性表明，二聚化过程是整体自组装过程的基础。我们的计算数据将肽缔合过程中的构象转换与实验中二聚体形成和随后的聚集倾向降低相关联。此外，我们的分析表明，单体激活不会先于肽缔合发生，因此表明，与单体转换模型相比，整个重折叠或增加相互作用模型更能真实地描述肽自组装过程。总之，我们的结果表明，早期肽寡聚物的构象转变代表肽自组装过程的瓶颈，因此突出了在淀粉样形成过程中对该反应进行结构表征的重要性。
