Polyglutamine Folding and Aggregation - Molecular Structure and Pathways

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Polyglutamine (or polyQ), a polymer consisting of glutamine repeat units, has been implicated in as many asnine neurodegenerative illnesses, including Huntington's disease (HD). An intriguing feature of the so-calledexpanded-polyQ-track diseases is that they only become manifest when the corresponding polyQ chainsexceed a certain critical length. Several hypotheses have been put forth to explain the onset of expandedpolyQdiseases. One hypothesis posits that, beyond a critical length, a polyQ molecule can adopt a foldedstructure that serves as a nucleus for the subsequent polymerization of additional molecules, thereby forming afibril. A more recent, alternative view proposes that several polyQ molecules can form a disordered aggregatethat, over time, gradually converts into a protofibril rich in ..-helical content. In this work, the PIs propose to use atomistic models of polyQ in aqueous solution to determine the structure of the nucleus and early aggregates, and to identify the molecular pathways throughwhich they form. More importantly, the PIs also propose to compare the results of simulations to 2-dimensionalinfrared (2D IR) spectroscopic measurements. To that end, the PIs will develop advanced simulation methods thatwill enable a thorough exploration of phase-space, as well as the pathways connecting different metastableconformational states, and they will develop tools that will permit prediction of 2D IR spectra directly from theresults of atomistic simulations. By engaging in a synergistic cycle of prediction and experimentation, they willarrive at a fundamental understanding of early-stage polyQ aggregation. Intellectual Merit: Theoretical and computational studies of the folding and aggregation of large PolyQmolecules in explicit water have been scarce. Studies of that nature, however, would provide much neededinsights into the genesis of a number of diseases. The research proposed will examine at an unprecedentedlevel of detail the ensembles of folded states adopted by polyQ, and will help determine how such states areinterconnected in the formation of small aggregates. The existence of such states and their dynamics will beassessed directly through 2D IR measurements, which will be interpreted in terms of the molecular modelsproposed in this work. The knowledge gained through this effort will not only provide insights into the onset ofHD, but will also yield important clues about the process of amyloid fibril formation by oligopeptides ingeneral. The computational challenges associated with our proposed research are staggering. A promisingarray of novel molecular modeling methods will be developed to meet those challenges. Such methods willadvance the state of the art in molecular simulation and will find applications in systems ranging frombiomolecules to complex fluids. The PIs anticipate that the combined 2D IR-computational approach to bedeveloped in this work will grow into a widely used technique for characterization of biomolecules.Broader Impacts: Huntington's disease currently afflicts 1 in 10,000 individuals. The toxic species are thesmall PolyQ aggregates of interest to this work; understanding the molecular origins of PolyQ folding andaggregation could provide new insights for development of therapeutic strategies. Beyond the beneficialimpact to society that would come with that understanding, the research proposed here offers a particularlyrelevant context in which to engage high-school children in science. The PIs propose to capitalize on thatopportunity by developing a workshop on protein aggregation and neurodegenerative disorders aimed at highschool students from under-represented minority backgrounds. By taking advantage of the computer expertiseof students involved in our proposed research, they will also propose to develop a strategy aimed at introducingmiddle-school and high-school students to computer programming early in their careers.