Transient Interdomain Interactions Modulate the Monomeric Structural Ensemble and Self-Assembly of Huntingtin Exon 1.

Polyglutamine (polyQ) tract length expansion (≥ 36 residues) within the N-terminal exon-1 of Huntingtin (Httex1) leads to Huntington's disease, a neurodegenerative condition marked by the presence of intranuclear Htt inclusions. Notably, the polyQ tract in Httex1 is flanked by an N-terminal coiled-coil domain -N17 (17 amino acids), which promotes the formation of soluble oligomers and brings the aggregation-prone polyQ tracts in close proximity. However, the molecular mechanisms underlying the conversion of soluble oligomers into insoluble β-rich aggregates with increasing polyQ length, remain unclear. In this study, extensive atomistic molecular dynamics (MD) simulations (aggregate time ≈0.7 milliseconds) are performed to uncover the interplay between structural transformation and domain "cross-talk" on the conformational ensemble and oligomerization of Httex1 due to polyQ expansion. Notably, MD-derived ensembles of N17-Qn-P5 monomers validated against NMR indicated that in addition to elevated α-helicity, polyQ expansion also favored transient, interdomain (N17/polyQ) interactions which resulted in the emergence of β-sheet conformations. Further, interdomain interactions modulated the stability of N17-mediated polyQ dimers and promoted a heterogeneous dimerization landscape. Finally, it is observed that the intact C-terminal proline-rich domain (PRD) promoted condensation of Httex1 through self-interactions involving its P10/P11 tracts while also interacting with N17 to suppress its α-helicity.