Unraveling the Molecular Complexity of N-Terminus Huntingtin Oligomers: Insights into Polymorphic Structures

Abstract

Huntington’s disease is a fatal neurodegenerative disease caused by an aberrant polyQ expansion in the Huntingtin protein (htt). In cases with polyQ≥35, the expanded polyQ tract misfolds and forms large intra-cellular aggregates. Despite significant attention, no clear consensus has been reached on the aggregate structures of the Huntingtin exon 1 protein fragments. Here, we apply coarse grained molecular dynamics to examine the mechanisms driving the aggregation process and resulting aggregate structures of 5 different N17 + polyQ systems, with polyQ lengths of 7, 15, 35, 40 and 45, using the ProMPT forcefield. Elongation of the polyQ domain results in an increase inβ-sheet rich structures. At longer polyQ lengths, intra-molecularβ-sheets are preferred over inter-molecular sheets, due to the collapse of the elongated polyQ domain into hairpin rich conformations. Crucially, we have discovered that changes in the polyQ length affect the resulting aggregated structure. With short polyQ domains, the N17 domains of htt bundle together, forming a hydrophobic core. As the polyQ length increases, competition between the hydrophobic interactions of N17 and the polar interactions of polyQ arises, leading to a tightly packed polyQ core, with an external distribution of the N17 domains. These findings can help explain the toxic gain-of function that mutant htt acquires.Author summaryIn this work, we consider 5 huntingtin peptide systems-N17 with polyQ lengths of 7, 15 35, 40 and 45, and examine structural characteristics of both the monomeric and aggregated peptide systems. We observe the presence of helices andβ-sheet in the polyQ domain. Most importantly, we discovered that the polyQ length affects the resultant aggregate structure. With short polyQ lengths, there is a competition between the hydrophobic interactions of N17 and the polar interactions of the polyQ domain, leading to a bundling of the N17 domains. At longer lengths of polyQ, the polar interactions dominate leading to a loss of N17 bundling and external distribution of the N17 domains. We suspect these variations in the aggregate morphology could explain possible downstream effects in Huntington’s disease pathology.