Polyglutamine (polyQ) expansion in exon1 (XN1) of the huntingtin protein is linked to Huntington's disease. When the number of glutamines exceeds a threshold of approximately 36–40 repeats, XN1 can readily form amyloid aggregates similar to those associated with disease. Many experiments suggest that misfolding of monomeric XN1 plays an important role in the length-dependent aggregation. Elucidating the misfolding of a XN1 monomer can help determine the molecular mechanism of XN1 aggregation and potentially help develop strategies to inhibit XN1 aggregation. The flanking sequences surrounding the polyQ region can play a critical role in determining the structural rearrangement and aggregation mechanism of XN1. Few experiments have studied XN1 in its entirety, with all flanking regions. To obtain structural insights into the misfolding of XN1 toward amyloid aggregation, we perform molecular dynamics simulations on monomeric XN1 with full flanking regions, a variant missing the polyproline regions, which are hypothesized to prevent aggregation, and an isolated polyQ peptide (Qn). For each of these three constructs, we study glutamine repeat lengths of 23, 36, 40 and 47. We find that polyQ peptides have a positive correlation between their probability to form a β-rich misfolded state and their expansion length. We also find that the flanking regions of XN1 affect its probability to^x_page_count=28 form a β-rich state compared to the isolated polyQ. Particularly, the polyproline regions form polyproline type II helices and decrease the probability of the polyQ region to form a β-rich state. Additionally, by lengthening polyQ, the first N-terminal 17 residues are more likely to adopt a β-sheet conformation rather than an α-helix conformation. Therefore, our molecular dynamics study provides a structural insight of XN1 misfolding and elucidates the possible role of the flanking sequences in XN1 aggregation.
Huntington's Disease is a neurodegenerative disorder associated with protein aggregation in neurons. The aggregates formed are thought to lead to neurotoxicity and cell death. Understanding the molecular structure of these aggregates may lead to strategies to inhibit aggregation. Exon 1 (XN1) of the huntingtin protein is critical for aggregate formation. This polypeptide has a naturally occurring polyglutamine sequence (polyQ), which is elongated in patients afflicted with the disease. The polyQ region in XN1 has several flanking sequences with distinct physicochemical properties, including the N-terminal 17 residues, two polyproline regions, and C-terminal sequences, that may affect its overall structure and aggregation. What is the overall structure of XN1, and what structural effects do the neighboring sequences have on each other and polyQ? We address these questions by studying computational models of various polypeptides, including XN1 and three mutant forms associated with Huntington's Disease. Certain neighboring sequences are found to inhibit aggregation, while others may be recruited by polyQ to form aggregates. Our results suggest the role that the flanking sequences may play in XN1 aggregation and may subsequently guide future structural models of XN1 aggregation.