Long polyglutamine (PolyQ) chains have been associated with a number of neurodegenerative diseases, most notably Huntington's Disease. Under some circumstances, these peptides fold onto themselves adopting a metastable conformation that is believed to be the nucleus for subsequent polymerization of additional chains. The molecular mechanisms behind such a nucleated growth polymerization process is not well understood. Literature studies concur in that a better understanding of the thermodynamics and kinetics of PolyQ folding and aggregation will accelerate the development of therapeutic treatments for Huntington's and other expanded PolyQ diseases.

The structure of the nucleus has not been elucidated yet, but two main candidates stand out from the experimental studies: the beta-helix and the beta-sheet. We have studied the folding pathways of a 54 residue polyglutamine (PolyQ) chain into a beta-helical structure using Transition Path Sampling (TPS) Monte Carlo simulations. The folding process of polyglutamine was examined in both explicit water and an implicit solvent. Both models revealed that the formation of a few critical contacts is necessary and sufficient for the molecule to fold. Once the primary contacts are formed, the fate of the protein is sealed and it is largely committed to fold.

To complement the studies mentioned above, we will present results from a comparative study in which we have performed equilibrium simulations of the two candidate structures as well as the unfolded structure in order to examine the differences in stability due to hydrogen bonding and peptide-water interactions. In addition, the effects of chain length on the conformational equilibrium of the molecule are explored via replica exchange molecular dynamics simulations of various chain lengths. Ultimately, our goal is to obtain TPS results for the beta-sheet-to-coil transition and compare them to the results obtained for the beta-helix-to-coil transition to elucidate the most stable structure for the nucleus of the PolyQ aggregates. Preliminary data will be presented on this.

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