Melquiond Adrien, Mousseau Normand, Derreumaux Philippe
Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Institut de Biologie Physico-Chimique et Université Paris 7, 13 rue Pierre et Marie Curie, 75005 Paris, France.
Proteins. 2006 Oct 1;65(1):180-91. doi: 10.1002/prot.21100.
Alzheimer's, Parkinson's, and Creutzfeldt-Jakob's neurodegenerative diseases are all linked with the assembly of normally soluble proteins into amyloid fibrils. Because of experimental limitations, structural characterization of the soluble oligomers, which form early in the process of fibrillogenesis and are cytotoxic, remains to be determined. In this article, we study the aggregation paths of seven chains of the shortest amyloid-forming peptide, using an activitated method and a reduced atomic representation. Our simulations show that disordered KFFE monomers ultimately form three distinct topologies of similar energy: amorphous oligomers, incomplete rings with beta-barrel character, and cross-beta-sheet structures with the meridional but not the equatorial X-ray fiber reflections. The simulations also shed light on the pathways from misfolded aggregates to fibrillar-like structures. They also underline the multiplicity of building blocks that can lead to the formation of the critical nucleus from which rapid growth of the fibril occurs.
阿尔茨海默病、帕金森病和克雅氏神经退行性疾病均与正常可溶性蛋白质组装成淀粉样纤维有关。由于实验限制，在纤维形成过程早期形成且具有细胞毒性的可溶性寡聚体的结构特征仍有待确定。在本文中，我们使用一种活化方法和简化的原子表示法研究了最短的淀粉样形成肽的七条链的聚集路径。我们的模拟表明，无序的KFFE单体最终形成三种能量相似的不同拓扑结构：无定形寡聚体、具有β-桶状特征的不完整环以及具有子午向而非赤道向X射线纤维反射的交叉β-片层结构。模拟还揭示了从错误折叠的聚集体到纤维状结构的途径。它们还强调了多种构建块可导致形成关键核，由此发生纤维的快速生长。
