Polyglutamine Monomer Structure and its Implications for Molecular Self-Assembly

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 geometryand 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. Acknowledgements: A great deal of thanks goes out to my supervisors, Dr. Stuart M. Rothstein and Dr. Heather Gordon, for all of the helpful guidance and suggestions that they have provided over the course of my thesis research. Thanks also goes out to Dr. Adonis Skandalis, Daniel Oblinsky, and to our Japanese collaborators, Dr. Shigenori Tanaka and his students.