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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Differential hydrophobicity drives self-assembly in Huntington's disease
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Differential hydrophobicity drives self-assembly in Huntington's disease

机译：疏水性差异驱动亨廷顿氏病的自组装

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摘要

Identifying the driving forces and the mechanism of association of huntingtin-exon1, a close marker for the progress of Huntington's disease, is an important prerequisite to finding potential drug targets and, ultimately, a cure. We introduce here a modeling framework based on a key analogy of the physicochemical properties of the exon1 fragment to block copolymers. We use a systematic mesoscale methodology, based on dissipative particle dynamics, which is capable of overcoming kinetic barriers, thus capturing the dynamics of significantly larger systems over longer times than considered before. Our results reveal that the relative hydrophobicity of the poly(glutamine) block as compared with the rest of the (proline-based) exon1 fragment, ignored to date, constitutes a major factor in the initiation of the self-assembly process. We find that the assembly is governed by both the concentration of exon1 and the length of the poly(glutamine) stretch, with a low-length threshold for association, even at the lowest volume fractions we considered. Moreover, this self-association occurs irrespective of whether the glutamine stretch is in random-coil or hairpin configuration, leading to spherical or cylindrical assemblies, respectively. We discuss the implications of these results for reinterpretation of existing research within this context, including that the routes toward aggregation of exon1 may be distinct from those of the widely studied homopolymeric poly(glu-tamine) peptides.
机译：鉴定亨廷顿氏病进展的密切标志物亨廷顿-外显子1的驱动力和缔合机制，是寻找潜在药物靶标并最终治愈的重要先决条件。我们在此介绍基于exon1片段与嵌段共聚物的理化性质的关键类比的建模框架。我们使用基于耗散粒子动力学的系统中尺度方法，该方法能够克服动力学障碍，从而在更长的时间内捕获比以前考虑的更大的系统的动力学。我们的结果表明，聚谷氨酰胺嵌段的相对疏水性与（基于脯氨酸的）外显子1片段的其余部分相比，迄今被忽略，是引发自组装过程的主要因素。我们发现该组装受外显子1的浓度和聚（谷氨酰胺）片段长度的控制，即使在我们考虑的最低体积分数下，缔合的阈值也很短。此外，不管谷氨酰胺伸展是无规线圈还是发夹构型，都发生这种自缔合，分别导致球形或圆柱形组装。我们讨论了这些结果对在这种情况下对现有研究的重新解释的含义，包括外显子1聚集的途径可能不同于广泛研究的均聚聚（谷氨酰胺）肽。

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