Transient interdomain interactions modulate the monomeric structural ensemble and self-assembly of Huntingtin Exon 1.

Polyglutamine 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 polyglutamine tract in Httex1 is flanked by an N-terminal coiled-coil domain - N17 (17 amino acids), which undergoes self-association to promote the formation of soluble Httex1 oligomers and brings the aggregation-prone polyQ tracts in close spatial proximity. However, the mechanisms underlying the subsequent conversion of soluble oligomers into insoluble β-rich aggregates with increasing polyQ length, remain unclear. Current knowledge suggests that expansion of the polyQ tract increases its helicity, and this favors its oligomerization and aggregation. In addition, studies utilizing photocrosslinking, conformation-specific antibodies and a stable coiled-coil heterotetrametric system fused to polyQ indicate that domain "cross-talk" (i.e., interdomain interactions) may play a role in the emergence of toxic conformations and the conversion of Httex1 oligomers into fibrillar aggregates. Here, we performed extensive atomistic molecular dynamics (MD) simulations (aggregate time ~ 0.7 ms) to uncover the interplay between structural transformation and domain "cross-talk" on the conformational ensemble and oligomerization landscape of Httex1. Notably, our MD-derived ensembles of N17-polyQ monomers validated against