分子动力学模拟揭示了 Huntingtin 基因外显子 1 中聚谷氨酰胺长度依赖的构象变化：对环境共溶剂调节易聚集状态的启示
Molecular Dynamics Simulations Reveal PolyQ-Length-Dependent Conformational Changes in Huntingtin Exon-1: Implications for Environmental Co-Solvent Modulation of Aggregation-Prone States
AI总结：
本研究通过分子动力学模拟揭示了聚谷氨酰胺长度对 Huntingtin 外显子 1 构象变化的影响，并探讨了共溶剂对易聚集状态的调节作用。
摘要：
亨廷顿氏病（HD）是由 HTT 基因中的 CAG 重复扩增引起的，这会延长 Huntingtin（HTT）中的聚谷氨酰胺（polyQ）区域，并促进错误折叠和聚集。虽然 polyQ 长度依赖的聚集已得到充分证实，但聚集前的原子构象动力学仍不明确。在此，我们对包含 N17 域、临床相关长度的 polyQ 区域（Q21，野生型；Q40，成人发病阈值；Q70，儿童发病）以及 polyproline（polyP）区域的 HTT 外显子 1 构造进行了全原子分子动力学模拟。使用 OPLS-AA 力场，在显式 SPC/E 水中进行了四链多复制模拟，持续 100 ns。我们量化了回转半径（Rg）、溶剂可及表面积（SASA）、均方根偏差（RMSD）和蛋白质内氢键作为构象扩展和聚集倾向的代理。polyQ 扩张导致 Rg 和 SASA 的逐步增加，与更伸展、溶剂暴露的构象集一致。我们进一步测试了有机共溶剂（甲醇、己烷、三氯乙烯；0.5 到 1.0 M），这些共溶剂以溶剂依赖的方式调节了这些景观。三氯乙烯诱导了 Q21 和 Q40 的明显扩展，而甲醇在 Q21 上产生了轻微的压缩。到目前为止，这是首次系统研究共溶剂对 HTT 外显子 1 构象动力学影响的 MD 研究。尽管采样有限，无法得出确定的机理结论，但观察到的趋势表明，疏水性共溶剂可以将 HTT 外显子 1 倾向于更扩展的构象集，从而推动对 HD 中基因-环境调节的计算研究。
英文摘要：
Huntington's disease (HD) is caused by CAG-repeat expansion in HTT, which lengthens the polyglutamine (polyQ) tract in huntingtin (HTT) and promotes misfolding and aggregation. While polyQ-length-dependent aggregation is well established, the atomistic conformational dynamics preceding aggregation remain less defined. Here we perform all-atom molecular dynamics simulations of HTT exon-1 constructs containing the N17 domain, polyQ tracts of clinically relevant lengths (Q21, wildtype; Q40, adult onset threshold; Q70, juvenile onset), and the polyproline (polyP) region. Multi-copy simulations (four chains) were run for 100 ns in explicit SPC/E water using the OPLS-AA force field. We quantified radius of gyration (Rg), solvent-accessible surface area (SASA), root-mean-square deviation (RMSD), and intra-protein hydrogen bonds as proxies for conformational expansion and aggregation propensity. PolyQ expansion drove progressive increases in Rg and SASA, consistent with more extended, solvent-exposed ensembles. We further tested organic co-solvents (methanol, hexane, trichloroethylene; 0.5 to 1.0 M), which modulated these landscapes in a solvent-dependent manner. Trichloroethylene induced marked expansion in Q21 and Q40, whereas methanol produced mild compaction in Q21. To our knowledge, this is the first MD study to systematically examine co-solvent effects on HTT exon-1 conformational dynamics. Although limited sampling precludes definitive mechanistic conclusions, the observed trends suggest that hydrophobic co-solvents can bias HTT exon-1 toward more expanded ensembles, motivating computational studies of gene-environment modulation in HD.
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