Polyglutamine, a polymer consisting of glutamine monomers, has been implicated in a number of neurodegenerative diseases, including Huntington's Disease. In non-HD individuals, the Huntingtin protein typically exhibits a 19-residue long polyglutamine (PolyQ) sequence. Individuals whose Huntingtin protein exhibits a sequence longer than 36 residues develop Huntington's Disease. In aqueous solution, PolyQ molecules form multiple hydrogen bonds with water and adopt a random coil conformation. Under certain circumstances, however, a long PolyQ chain can hydrogen bond with itself and form a metastable folded structure that is believed to act as a nucleus for subsequent aggregation or polymerization of additional PolyQ molecules, thereby leading to the formation of aggregates whose characteristics are reminiscent of amyloid fibrils. It has also been suggested that, once formed, the folded nucleus facilitates the folding of additional chains, leading to a rapid elongation of the aggregates. The precise nature of that folded metastable state and the mechanism behind its formation remain unknown. Literature studies, however, concur in that elucidating the structure of the folded PolyQ nucleus is essential for understanding PolyQ aggregation and the onset of Huntington's Disease. The project seeks to determine the structure of that nucleus and, more importantly, the path through which it appears. The project also proposes to investigate if and how a folded nucleus might mediate or induce the folding of additional chains, and the early stages of chain aggregation. A carefully conceived molecular modeling approach is proposed, in which detailed atomistic models of polyglutamine and advanced simulation techniques will be used towards such ends. The PIs anticipate that a relatively complete, molecular-level mechanistic explanation of PolyQ folding and early-stage aggregation will emerge from our studies. Preliminary results already reveal exciting and unprecedented insights into the pathways through which PolyQ folds.
Intellectual Merit: Theoretical and computational studies of PolyQ folding and aggregation have been scarce. Studies of that nature offer the distinct possibility of providing important insights into the structure of folded PolyQ molecules, their aggregates, and the respective folding processes. The research outlined in this project will examine at an unprecedented level of molecular detail the ensemble of trajectories or protein conformations that constitute the transition state ensemble for the folding and aggregation of PolyQ. The knowledge gained through this effort will not only provide insights into the onset of Huntington's Disease, but it might also provide important clues about the process of amyloid fibril formation in general. The computational challenges associated with our proposed research are staggering. A promising array of novel molecular modeling methods will be developed to meet those challenges. Such methods will advance the state of the art in molecular modeling and scientific computing, and will find wide ranging applications in a wide variety of systems, ranging from biomolecules to complex fluids.
Broader Impacts: Huntington's disease currently afflicts 1 in 10,000 individuals. Highly toxic PolyQ oligomers are believed to be responsible for the onset of the disease. Understanding the molecular origins of PolyQ folding and oligomer formation will provide important insights that may help in the development of therapeutic strategies. Beyond the inherent impact to society that would arise from discovering the mechanism of PolyQ folding, the research proposed here offers a particularly relevant forum in which to disseminate the benefits of fundamental molecular-level research to society. The PIs propose to capitalize on that opportunity by developing a workshop on protein aggregation and neurodegenerative disorders aimed at high school students from under-represented minority backgrounds. 1
