dorsal/arxiv
View SchemaDifferential hydrophobicity drives self-assembly in Huntington's disease
| Authors | Martin G. Burke, Rudiger Woscholski, Sophia N. Yaliraki |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0309017 |
| URL | https://arxiv.org/abs/q-bio/0309017 |
| DOI | 10.1073/pnas.1936025100 |
Abstract
Identifying the driving forces and the mechanism of association of huntingtin-exon1, a close marker for the progress of Huntington's disease, is an important prerequisite towards finding potential drug targets, and ultimately a cure. We introduce here a modelling framework based on a key analogy of the physico-chemical properties of the exon1 fragment to block copolymers. We use a systematic mesoscale methodology, based on Dissipative Particle Dynamics, which is capable of overcoming kinetic barriers, thus capturing the dynamics of significantly larger systems over longer times than considered before. Our results reveal that the relative hydrophobicity of the poly-glutamine block as compared to the rest of the (proline-based) exon1 fragment, ignored to date, constitutes a major factor in the initiation of the self-assembly process. We find that the assembly is governed by both the concentration of exon1 and the length of the poly-glutamine stretch, with a low length threshold for association even at the lowest volume fractions we considered. Moreover, this self-association occurs irrespective of whether the glutamine stretch is in random coil or hairpin configuration, leading to spherical or cylindrical assemblies, respectively. We discuss the implications of these results for reinterpretation of existing research within this context, including that the routes towards aggregation of exon1 may be distinct to those of the widely studied homopolymeric poly-glutamine peptides.
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"abstract": "Identifying the driving forces and the mechanism of association of\nhuntingtin-exon1, a close marker for the progress of Huntington\u0027s disease, is\nan important prerequisite towards finding potential drug targets, and\nultimately a cure. We introduce here a modelling framework based on a key\nanalogy of the physico-chemical properties of the exon1 fragment to block\ncopolymers. We use a systematic mesoscale methodology, based on Dissipative\nParticle Dynamics, which is capable of overcoming kinetic barriers, thus\ncapturing the dynamics of significantly larger systems over longer times than\nconsidered before. Our results reveal that the relative hydrophobicity of the\npoly-glutamine block as compared to the rest of the (proline-based) exon1\nfragment, ignored to date, constitutes a major factor in the initiation of the\nself-assembly process. We find that the assembly is governed by both the\nconcentration of exon1 and the length of the poly-glutamine stretch, with a low\nlength threshold for association even at the lowest volume fractions we\nconsidered. Moreover, this self-association occurs irrespective of whether the\nglutamine stretch is in random coil or hairpin configuration, leading to\nspherical or cylindrical assemblies, respectively. We discuss the implications\nof these results for reinterpretation of existing research within this context,\nincluding that the routes towards aggregation of exon1 may be distinct to those\nof the widely studied homopolymeric poly-glutamine peptides.",
"arxiv_id": "q-bio/0309017",
"authors": [
"Martin G. Burke",
"Rudiger Woscholski",
"Sophia N. Yaliraki"
],
"categories": [
"q-bio.BM"
],
"doi": "10.1073/pnas.1936025100",
"title": "Differential hydrophobicity drives self-assembly in Huntington\u0027s disease",
"url": "https://arxiv.org/abs/q-bio/0309017"
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