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Notably, the polyQ tract in Httex1 is flanked by an N\u2010terminal coiled\u2010coil domain \u2013N17 (17 amino acids), which promotes the formation of soluble oligomers and brings the aggregation\u2010prone polyQ tracts in close proximity. However, the molecular mechanisms underlying the conversion of soluble oligomers into insoluble \u03b2\u2010rich aggregates with increasing polyQ length, remain unclear. In this study, extensive atomistic molecular dynamics (MD) simulations (aggregate time \u22480.7 milliseconds) are performed to uncover the interplay between structural transformation and domain \u201ccross\u2010talk\u201d on the conformational ensemble and oligomerization\u00a0of Httex1 due to polyQ expansion. Notably, MD\u2010derived ensembles of N17\u2010Q\n                    <jats:sub>n<\/jats:sub>\n                    \u2010P\n                    <jats:sub>5<\/jats:sub>\n                    monomers validated against NMR\u00a0indicated that in addition to elevated \u03b1\u2010helicity, polyQ expansion also favored transient, interdomain (N17\/polyQ) interactions which resulted\u00a0in the emergence of \u03b2\u2010sheet conformations. Further, interdomain interactions modulated the stability of N17\u2010mediated polyQ dimers and promoted a heterogeneous dimerization landscape. Finally, it is observed that the intact C\u2010terminal proline\u2010rich domain (PRD) promoted condensation of Httex1 through self\u2010interactions involving its P\n                    <jats:sub>10<\/jats:sub>\n                    \/P\n                    <jats:sub>11<\/jats:sub>\n                    \u00a0tracts while also interacting with N17 to suppress its \u03b1\u2010helicity.\n                  <\/jats:p>","DOI":"10.1002\/advs.202501462","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T03:39:17Z","timestamp":1745811557000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Transient Interdomain Interactions Modulate the Monomeric Structural Ensemble and Self\u2010Assembly of Huntingtin Exon 1"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3919-3527","authenticated-orcid":false,"given":"Priyesh","family":"Mohanty","sequence":"first","affiliation":[{"name":"Artie McFerrin Department of Chemical Engineering Texas A&amp;M University  College Station TX 77843 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8608-7359","authenticated-orcid":false,"given":"Tien Minh","family":"Phan","sequence":"additional","affiliation":[{"name":"Artie McFerrin Department of Chemical Engineering Texas A&amp;M University  College Station TX 77843 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9725-6402","authenticated-orcid":false,"given":"Jeetain","family":"Mittal","sequence":"additional","affiliation":[{"name":"Artie McFerrin Department of Chemical Engineering Texas A&amp;M University  College Station TX 77843 USA"},{"name":"Department of Chemistry Texas A&amp;M University  College Station TX 77843 USA"},{"name":"Interdisciplinary Graduate Program in Genetics and Genomics Texas A&amp;M University  College Station TX 77843 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