Molecular Dynamics Simulations Reveal PolyQ-Length-Dependent Conformational Changes in Huntingtin Exon-1: Implications for Environmental Co-Solvent Modulation of Aggregation-Prone States

2026-03-02

AI Summary

The polyglutamine (polyQ) length–dependent conformational dynamics of huntingtin exon-1 in Huntington’s disease and their modulation by environmental cosolvents remain poorly understood. This study employs all-atom molecular dynamics simulations (OPLS-AA force field with SPC/E water model) to systematically investigate the conformational behavior of three polyQ variants—Q21, Q40, and Q70—in aqueous solution and in the presence of organic cosolvents such as trichloroethylene and methanol. The results demonstrate that polyQ elongation leads to more extended conformations with increased solvent exposure. Hydrophobic cosolvents markedly promote extended states, whereas methanol induces a slight compaction specifically in Q21. This work provides the first atomic-level evidence of cosolvent-mediated regulation of huntingtin exon-1 conformation, offering novel mechanistic insights into how gene–environment interactions may influence protein aggregation in Huntington’s disease.

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• Cognitive Modeling & Cognitive Systems: Simulating Human Behavior
• Search and Optimization: Sampling/Simulation-based Search
• Application Domains: Humanities & Computational Social Science

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• Economics, Online Markets and Human Computation: Data quality aspects of human-annotated datasets
• Web Mining and Content Analysis: Web data generation and simulation
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Abstract

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.

Problem

• Huntington's disease
• polyglutamine expansion
• conformational dynamics
• aggregation-prone states
• environmental co-solvents

Innovation

• molecular dynamics simulations
• polyglutamine expansion
• co-solvent modulation
• conformational dynamics
• Huntingtin exon-1