Helix Mediated Aggregation in Poly-Glutamine Tracts

In protein aggregation related neurodegenerative diseases, a disease specific host protein misfolds and adopts a metastable, aggregation prone conformation. For Huntington's disease, the htt exon I domain is the smallest physiological N-terminal fragment that forms disease related poly-glutamine rich fibrils. Exon I consists of a glutamine tract, flanked by a 17 amino acid long fragment (httNT) and a proline rich fragment. The presence of httNT fragment has been shown to significantly accelerate the formation of poly-glutamine rich fibrils. In this study, we test the helix mediated aggregation mechanism of glutamine tracts as proposed by the Wetzel group by using molecular dynamics simulations. Analysis of httNT fragment in bulk water suggests only a weak helix propensity. However, when several fragments come into contact they adopt the alpha-helix conformation and form bundles. When the httNT fragment is flanked to the poly-glutamine tract, these bundles lead to a dramatic increase in glutamine concentration. By using a coarse grained model, we study the beta-sheet formation and show that, In agreement with the Wetzel group's hypothesis, beta-sheet propensity significantly increases in these bundles compared to the isolated poly-glutamine tracts.