De Simone Alfonso, Esposito Luciana, Pedone Carlo, Vitagliano Luigi
Istituto di Biostrutture e Bioimmagini, CNR, and Dipartimento delle Scienze Biologiche, Università Federico II, I-80134 Naples, Italy.
Biophys J. 2008 Aug;95(4):1965-73. doi: 10.1529/biophysj.108.129213. Epub 2008 May 9.
Deposition of insoluble amyloid plaques is frequently associated with a large variety of neurodegenerative diseases. However, data collected in the last decade have suggested that the neurotoxic action is exerted by prefibrillar, soluble assemblies of amyloid-forming proteins and peptides. The scarcity of structural data available for both amyloid-like fibrils and soluble oligomers is a major limitation for the definition of the molecular mechanisms linked to the onset of these diseases. Recently, the structural characterization of GNNQQNY and other peptides has shown a general feature of amyloid-like fibers, the so-called steric zipper motif. However, very little is known still about the prefibrillar oligomeric forms. By using replica exchange molecular dynamics we carried out extensive analyses of the properties of several small and medium GNNQQNY aggregates arranged through the steric zipper motif. Our data show that the assembly formed by two sheets, each made of two strands, arranged as in the crystalline states are highly unstable. Conformational free energy surfaces indicate that the instability of the model can be ascribed to the high reactivity of edge backbone hydrogen bonding donors/acceptors. On the other hand, data on larger models show that steric zipper interactions may keep small oligomeric forms in a stable state. These models simultaneously display two peculiar structural motifs: a tightly packed steric zipper interface and a large number of potentially reactive exposed strands. The presence of highly reactive groups on these assemblies likely generates two distinct evolutions. On one side the reactive groups quickly lead, through self-association, to the formation of ordered fibrils, on the other they may interfere with several cellular components thereby generating toxic effects. In this scenario, fiber formation propensity and toxicity of oligomeric states are two different manifestations of the same property: the hyper-reactivity of the exposed strands.
不溶性淀粉样斑块的沉积常常与多种神经退行性疾病相关。然而，过去十年收集的数据表明，神经毒性作用是由淀粉样蛋白和肽的前纤维、可溶性聚集体施加的。可用于淀粉样样纤维和可溶性寡聚体的结构数据的稀缺是定义与这些疾病发病相关的分子机制的主要限制。最近，GNNQQNY和其他肽的结构表征显示了淀粉样样纤维的一个普遍特征，即所谓的空间拉链基序。然而，对于前纤维寡聚体形式仍然知之甚少。通过使用副本交换分子动力学，我们对通过空间拉链基序排列的几种中小尺寸GNNQQNY聚集体的性质进行了广泛分析。我们的数据表明，由两片组成的聚集体，每片由两条链组成，如在晶体状态下排列，是高度不稳定的。构象自由能表面表明，模型的不稳定性可归因于边缘主链氢键供体/受体的高反应性。另一方面，更大模型的数据表明，空间拉链相互作用可能使小的寡聚体形式保持在稳定状态。这些模型同时显示出两个独特的结构基序：紧密堆积的空间拉链界面和大量潜在反应性暴露链。这些聚集体上高反应性基团的存在可能产生两种不同的演变。一方面，反应性基团通过自缔合迅速导致有序纤维的形成，另一方面，它们可能干扰几种细胞成分，从而产生毒性作用。在这种情况下，纤维形成倾向和寡聚体状态的毒性是同一性质的两种不同表现：暴露链的高反应性。
