Polyglutamine expansion (≥ 36 residues) within the N-terminal exon-1 of Huntingtin (Httex1) leads to Huntington's disease, a neurogenerative 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 conformation-specific antibodies and a stable coiled-coil heterotetrametric system fused to polyQ indicate that domain "cross-talk" (i.e., interdomain interactions) may be necessary to efficiently promote the emergence of toxic conformations (in monomers and oligomers) and fibrillar aggregation. Here, we performed extensive atomistic molecular dynamics (MD) simulations (aggregate time ∼ 0.7 ms) of N17-polyQ fragments to uncover the interplay between structural transformation and domain "cross-talk" on the monomeric structural ensemble and oligomerization landscape of Httex1. Our simulation ensembles of N17-polyQ monomers validated against 13 C NMR chemical shifts indicated that in addition to elevated α-helicity, polyQ expansion also favors transient, interdomain (N17-polyQ) interactions which result in the emergence of β-conformations. Further, interdomain interactions decreased the overall stability of N17-mediated dimers by counteracting the stabilizing effect of increased α-helicity and promoted a heterogenous oligomerization landscape on the sub-microsecond timescale. Overall, our study uncovers the significance of domain "cross-talk" in modulating the monomeric conformational ensemble and oligomerization landscape of Httex1 to favor the formation of amyloid aggregates.