Molecular dynamics analysis of the aggregation propensity of polyglutamine segments.
Molecular dynamics analysis of the aggregation propensity of polyglutamine segments.
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DOI：
10.1371/journal.pone.0178333
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Facelli JC
中科院分区：
文献类型：
--
作者：
Wen J;Scoles DR;Facelli JC
蛋白质错误折叠和聚集是至少十种聚谷氨酰胺（polyQ）神经退行性疾病共有的致病特征。虽然溶剂-溶液相互作用是驱动蛋白质折叠和聚集的关键因素，但扩展的 PolyQ 束的溶剂化特性尚不清楚。通过在显式溶剂环境中使用 GPU 支持的 PolyQ 单体的全原子分子动力学模拟，本研究表明，随着 PolyQ 束长度的增加，溶剂与 PolyQ 相互作用的倾向降低。这项研究发现，具有较长polyQ片段的polyQ序列中相距较远的残基之间的长距离相互作用占主导地位，这导致了显着的构象差异。这项研究还表明，由平行β结构组成的大环出现在长polyQ束中，并呈现出新的聚合构建块，其聚合由长距离polyQ内相互作用驱动。最后，与之前使用粗粒度模拟的观察结果一致，本研究表明，随着 PolyQ 长度的增加，聚集倾向有所增加，并且这种增加与溶剂-PolyQ 相互作用能力的降低相关。这些结果表明调节溶剂-polyQ相互作用作为治疗polyQ疾病的一种可能的治疗策略。
Protein misfolding and aggregation is a pathogenic feature shared among at least ten polyglutamine (polyQ) neurodegenerative diseases. While solvent-solution interaction is a key factor driving protein folding and aggregation, the solvation properties of expanded polyQ tracts are not well understood. By using GPU-enabled all-atom molecular dynamics simulations of polyQ monomers in an explicit solvent environment, this study shows that solvent-polyQ interaction propensity decreases as the lengths of polyQ tract increases. This study finds a predominance in long-distance interactions between residues far apart in polyQ sequences with longer polyQ segments, that leads to significant conformational differences. This study also indicates that large loops, comprised of parallel β-structures, appear in long polyQ tracts and present new aggregation building blocks with aggregation driven by long-distance intra-polyQ interactions. Finally, consistent with previous observations using coarse-grain simulations, this study demonstrates that there is a gain in the aggregation propensity with increased polyQ length, and that this gain is correlated with decreasing ability of solvent-polyQ interaction. These results suggest the modulation of solvent-polyQ interactions as a possible therapeutic strategy for treating polyQ diseases.