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| Format: | Preprint |
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2026
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| Online Access: | https://arxiv.org/abs/2603.02572 |
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| _version_ | 1866915830767288320 |
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| author | Geddes-Nelson, Jai Liu, Xiaochen Yong, Ken-Tye |
| author_facet | Geddes-Nelson, Jai Liu, Xiaochen Yong, Ken-Tye |
| contents | 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. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2603_02572 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | Molecular Dynamics Simulations Reveal PolyQ-Length-Dependent Conformational Changes in Huntingtin Exon-1: Implications for Environmental Co-Solvent Modulation of Aggregation-Prone States Geddes-Nelson, Jai Liu, Xiaochen Yong, Ken-Tye Computational Engineering, Finance, and Science Biomolecules 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. |
| title | Molecular Dynamics Simulations Reveal PolyQ-Length-Dependent Conformational Changes in Huntingtin Exon-1: Implications for Environmental Co-Solvent Modulation of Aggregation-Prone States |
| topic | Computational Engineering, Finance, and Science Biomolecules |
| url | https://arxiv.org/abs/2603.02572 |