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.

翻译：亨廷顿病（HD）由HTT基因中CAG重复序列扩增引起，该突变导致亨廷顿蛋白（HTT）的多聚谷氨酰胺（polyQ）片段延长，进而促进蛋白质错误折叠与聚集。尽管polyQ长度依赖性聚集已被充分证实，但聚集发生前的原子尺度构象动力学仍不明确。本研究对包含N17结构域、具有临床相关长度polyQ片段（Q21，野生型；Q40，成人发病阈值；Q70，青少年发病型）及多聚脯氨酸（polyP）区域的HTT外显子-1构建体进行了全原子分子动力学模拟。采用OPLS-AA力场在显式SPC/E水溶液中运行多拷贝模拟（四条链），时长100纳秒。我们通过回转半径（Rg）、溶剂可及表面积（SASA）、均方根偏差（RMSD）及蛋白质内氢键作为构象扩展与聚集倾向的量化指标。polyQ扩展导致Rg与SASA的渐进性增加，与更伸展、溶剂暴露的构象系综一致。我们进一步测试了有机共溶剂（甲醇、己烷、三氯乙烯；浓度0.5至1.0 M），这些溶剂以依赖溶剂种类的方式调控构象景观。三氯乙烯在Q21和Q40中引起显著扩展，而甲醇在Q21中产生轻微紧缩。据我们所知，这是首个系统研究共溶剂对HTT外显子-1构象动力学影响的分子动力学研究。尽管有限的采样无法得出确定性机制结论，但观察到的趋势表明疏水性共溶剂可能促使HTT外显子-1偏向更扩展的构象系综，这为开展亨廷顿病中基因-环境调控的计算研究提供了新思路。