Polyglutamine (or polyQ), a polymer consisting of glutamine repeat units, has been implicated in as many as nine neurodegenerative illnesses, including Huntington's disease (HD). An intriguing feature of the so-called expanded-polyQ-track diseases is that they only become manifest when the corresponding polyQ chains exceed a certain critical length. Several hypotheses have been put forth to explain the onset of expandedpolyQ diseases. One hypothesis posits that, beyond a critical length, a polyQ molecule can adopt a folded structure that serves as a nucleus for the subsequent polymerization of additional molecules, thereby forming a fibril. A more recent, alternative view proposes that several polyQ molecules can form a disordered aggregate that, 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 through which they form. More importantly, the PIs also propose to compare the results of simulations to 2-dimensional infrared (2D IR) spectroscopic measurements. To that end, the PIs will develop advanced simulation methods that will enable a thorough exploration of phase-space, as well as the pathways connecting different metastable conformational states, and they will develop tools that will permit prediction of 2D IR spectra directly from the results of atomistic simulations. By engaging in a synergistic cycle of prediction and experimentation, they will arrive at a fundamental understanding of early-stage polyQ aggregation.
Intellectual Merit: Theoretical and computational studies of the folding and aggregation of large PolyQ molecules in explicit water have been scarce. Studies of that nature, however, would provide much needed insights into the genesis of a number of diseases. The research proposed will examine at an unprecedented level of detail the ensembles of folded states adopted by polyQ, and will help determine how such states are interconnected in the formation of small aggregates. The existence of such states and their dynamics will be assessed directly through 2D IR measurements, which will be interpreted in terms of the molecular models proposed in this work. The knowledge gained through this effort will not only provide insights into the onset of HD, but will also yield important clues about the process of amyloid fibril formation by oligopeptides 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 simulation and will find applications in systems ranging from biomolecules to complex fluids. The PIs anticipate that the combined 2D IR-computational approach to be developed 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 the small PolyQ aggregates of interest to this work; understanding the molecular origins of PolyQ folding and aggregation could provide new insights for development of therapeutic strategies. Beyond the beneficial impact to society that would come with that understanding, the research proposed here offers a particularly relevant context in which to engage high-school children in science. 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. By taking advantage of the computer expertise of students involved in our proposed research, they will also propose to develop a strategy aimed at introducing middle-school and high-school students to computer programming early in their careers.
