Polyglutamine is a naturally occurring peptide found within several proteins in
neuronal cells of the brain, and its aggregation has been implicated in several
neurodegenerative diseases, including Huntington's disease. The resulting aggregates
have been demonstrated to possess ~-sheet structure, and aggregation has been shown to
start with a single misfolded peptide. The current project sought to computationally
examine the structural tendencies of three mutant poly glutamine peptides that were
studied experimentally, and found to aggregate with varying efficiencies. Low-energy
structures were generated for each peptide by simulated annealing, and were analyzed
quantitatively by various geometry- and energy-based methods. According to the results,
the experimentally-observed inhibition of aggregation appears to be due to localized
conformational restraint placed on the peptide backbone by inserted prolines, which in
tum confines the peptide to native coil structure, discouraging transition towards the ~sheet
structure required for aggregation. Such knowledge could prove quite useful to the
design of future treatments for Huntington's and other related diseases