Low molecular weight oligomers of amyloid peptides display β-barrel conformations: A replica exchange molecular dynamics study in explicit solvent
Low molecular weight oligomers of amyloid peptides display β-barrel conformations: A replica exchange molecular dynamics study in explicit solvent
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DOI：
10.1063/1.3385470
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发表时间：
2010-04-28
影响因子：
4.4
通讯作者：
Derreumaux, Philippe
中科院分区：
文献类型：
--
作者：
De Simone, Alfonso;Derreumaux, Philippe
蛋白质和肽自组装成淀粉样原纤维与 40 多种病理状况有关，包括神经退行性疾病和系统性淀粉样变性。在聚集的早期步骤中形成的扩散性低分子量蛋白质和肽寡聚物似乎是这些疾病的分子病因学中的有害细胞毒性物质。到目前为止，由于这些低聚物的瞬态和动态特征，其结构表征仍然难以捉摸。我们在这里通过完全原子复制品交换分子动力学模拟，研究了来自 beta-2 微球蛋白的淀粉样肽 NHVTLSQ 七聚体的能量景观。总计 5 μs 的模拟表明，显式溶剂中的低分子量低聚物由与无定形态和原纤维状组件处于平衡状态的 β 桶组成。这些结果还解释了 pH 对构象特性的影响，为淀粉样蛋白形成系统的早期聚集步骤中瞬时 β-桶组件的形成提供了强有力的证据。我们的研究结果是根据寡聚物的细胞毒性进行讨论的。 (C) 2010 年美国物理研究所。 [号码：10.1063/1.3385470]
The self-assembly of proteins and peptides into amyloid fibrils is connected to over 40 pathological conditions including neurodegenerative diseases and systemic amyloidosis. Diffusible, low molecular weight protein and peptide oligomers that form in the early steps of aggregation appear to be the harmful cytotoxic species in the molecular etiology of these diseases. So far, the structural characterization of these oligomers has remained elusive owing to their transient and dynamic features. We here address, by means of full atomistic replica exchange molecular dynamics simulations, the energy landscape of heptamers of the amyloidogenic peptide NHVTLSQ from the beta-2 microglobulin protein. The simulations totaling 5 mu s show that low molecular weight oligomers in explicit solvent consist of beta-barrels in equilibrium with amorphous states and fibril-like assemblies. The results, also accounting for the influence of the pH on the conformational properties, provide a strong evidence of the formation of transient beta-barrel assemblies in the early aggregation steps of amyloid-forming systems. Our findings are discussed in terms of oligomers cytotoxicity. (C) 2010 American Institute of Physics. [doi: 10.1063/1.3385470]