Simulation of the Effects of Flanking Sequences on Polyglutamine Aggregation

Huntington's disease is one of a set of nine progressive neurodegenerative diseases caused by the expansion of CAG sequence repeats. This results in affected proteins with abnormally long polyglutamine (polyQ) tracts, which beyond a pathological threshold length form toxic aggregates.~Recent experimental studies suggest the sequences flanking the polyQ tract have a profound impact on the aggregation rates and morphologies. The 17 residues N terminus to the polyQ insert in the huntingtin protein (Htt) have been shown to accelerate aggregation, particularly the formation of insoluble fibrils.~The proline-rich C terminal region has been demonstrated to slow the rate of aggregation.~We propose a coarse-grain model of the polyQ tract, with and without its N and C terminal regions, and utilize Brownian dynamics simulation to examine the kinetics of aggregation.