title: Folding of polyglutamine chains.
abstract: Long polyglutamine chains have been associated with a number of neurodegenerative diseases. These include Huntington's disease, where expanded polyglutamine (PolyQ) sequences longer than 36 residues are correlated with the onset of symptoms. In this paper we study the folding pathway of a 54-residue PolyQ chain into a beta-helical structure. Transition path sampling Monte Carlo simulations are used to generate unbiased reactive pathways between unfolded configurations and the folded beta-helical structure of the polyglutamine chain. The folding process is examined in both explicit water and an implicit solvent. Both models reveal 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. We find that, consistent with emerging hypotheses about PolyQ aggregation, a stable beta-helical structure could serve as the nucleus for subsequent polymerization of amyloid fibrils. Our results indicate that PolyQ sequences shorter than 36 residues cannot form that nucleus, and it is also shown that specific mutations inferred from an analysis of the simulated folding pathway exacerbate its stability.
authors.affiliation: Department of Chemical Engineering, University of Wisconsin, Madison, Wisconsin 53706-1691, USA.
authors.forename: Manan
authors.initials: M
authors.lastname: Chopra
authors.forename: Allam S
authors.initials: AS
authors.lastname: Reddy
authors.forename: N L
authors.initials: NL
authors.lastname: Abbott
authors.forename: J J
authors.initials: JJ
authors.lastname: de Pablo
mesh_terms: D008958:Models, Molecular; D009154:Mutation; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D044367:Phase Transition; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D010455:Peptides; C097188:polyglutamine