The Role of PolyQ in Global Conformational Dynamics and Stability of Huntingtin

Huntington's disease (HD) is known for its abnormal polyQ stretch in the first exon of the HTT gene. HD is listed among the fatal autosomal dominant neurodegenerative disorders targeting the central nervous system and interfering with motor, cognitive, and psychiatric functions. The HTT gene codes for Huntingtin (Htt), a large three-domain protein with a polyQ stretch present in the N-terminal domain. In diseased cells, inclusion bodies are enriched in Htt fragments containing an extended polyQ region. The expansion of the polyQ correlates with aggregate size and onset of HD. However, the exact role of the full-length Htt in aggregate formation has not been fully known. Using coarse-grained molecular dynamics simulations at the near-atom level, our study indicates that the conformational dynamics of Htt─twisting and open-close motions of the domains─are dependent on the length of polyQ. In the presence of HAP40, the global conformational landscape is restricted, and the degree of dependence on polyQ length is low. The intra- and intercontact analyses suggest that the polyQ region can loop like a hairpin with a higher probability for a larger polyQ length. However, the looping probability is reduced in the presence of HAP40 due to increased contacts between polyQ and other regions of Htt. Thus, our findings indicate that polyQ has a significant role in the disease's pathogenesis, which includes altered functional activity and structural modifications leading to inclusion body formation. These effects can be controlled with the help of HAP40.