Département de Physique and Groupe de recherche sur les protéines membranaires, Université de Montréal, C.P. 6128, succursale Centre-ville, Montréal (Québec), Canada.
J Phys Chem B. 2012 Oct 11;116(40):12168-79. doi: 10.1021/jp306661c. Epub 2012 Sep 28.
Several neurodegenerative diseases are associated with the polyglutamine (polyQ) repeat disorder in which a segment of consecutive glutamines in the native protein is produced with too many glutamines. Huntington's disease, for example, is related to the misfolding of the Huntingtin protein which occurs when the polyQ segment has more than approximately 36 glutamines. Experimentally, it is known that the polyQ segment alone aggregates into β-rich conformations such as amyloid fibrils. Its aggregation is modulated by the number of glutamine residues as well as by the surrounding amino acid sequences such as the 17-amino-acid N-terminal fragment of Huntingtin which increases the aggregation rate. Little structural information is available, however, regarding the first steps of aggregation and the atomistic mechanisms of oligomerization are yet to be described. Following previous coarse-grained replica-exchange molecular dynamics simulations that show the spontaneous formation of a nanotube consisting of two intertwined antiparallel strands (Laghaei, R.; Mousseau, N. J. Chem. Phys. 2010, 132, 165102), we study this configuration and some extensions of it using all-atom explicit solvent MD simulations. We compare two different lengths for the polyQ segment, 40 and 30 glutamines, and we investigate the impact of the Huntingtin N-terminal residues (htt(NT)). Our results show that the dimeric nanotubes can provide a building block for the formation of longer nanotubes (hexamers and octamers). These longer nanotubes are characterized by large β-sheet propensities and a small solvent exposure of the main-chain atoms. Moreover, the oligomerization between two nanotubes occurs through the formation of protein/protein H-bonds and can result in an elongation of the water-filled core. Our results also show that the htt(NT) enhances the structural stability of the β-rich seeds, suggesting a new mechanism by which it can increase the aggregation rate of the amyloidogenic polyQ sequence.
几种神经退行性疾病与多聚谷氨酰胺（polyQ）重复紊乱有关，其中天然蛋白中的一段连续谷氨酰胺产生过多的谷氨酰胺。例如，亨廷顿病与亨廷顿蛋白的错误折叠有关，当 polyQ 片段超过大约 36 个谷氨酰胺时，就会发生这种情况。实验表明，单独的 polyQ 片段会聚集形成富含β的构象，如淀粉样纤维。其聚集受谷氨酰胺残基的数量以及周围氨基酸序列的调节，如亨廷顿蛋白的 17 个氨基酸 N 端片段增加了聚集速率。然而，关于聚集的第一步和寡聚化的原子机制的结构信息很少，因此还需要描述。在先前的粗粒 replica-exchange 分子动力学模拟之后，这些模拟表明自发形成了由两个相互缠绕的反平行链组成的纳米管（Laghaei，R.；Mousseau，N. J. Chem. Phys. 2010，132，165102），我们使用全原子显式溶剂 MD 模拟研究了这种构象及其一些扩展。我们比较了两种不同长度的 polyQ 片段，40 和 30 个谷氨酰胺，并研究了亨廷顿蛋白 N 端残基（htt（NT））的影响。我们的结果表明，二聚体纳米管可以为形成更长的纳米管（六聚体和八聚体）提供构建块。这些较长的纳米管的特点是具有较大的β-片倾向和主链原子的小溶剂暴露。此外，两个纳米管之间的寡聚化是通过形成蛋白质/蛋白质氢键发生的，并且可以导致充满水的核心的伸长。我们的结果还表明，htt（NT）增强了富含β的种子的结构稳定性，这表明它可以增加淀粉样蛋白 polyQ 序列的聚集速率的新机制。
