Polyglutamine mediated aggregation is central to the onset and progression of at least nine distinct neurodegenerative disorders. Through a combination of theory, experiment, and atomistic simulations we have uncovered synergies between polyglutamine tracts and flanking sequence modules as modulators of the driving forces, solubility boundaries, aggregation kinetics, and aggregate morphologies. The focus of these investigations has been on the exon 1 encoded N-terminal region of the protein huntingtin. Our biophysical studies thus far have provided insights into the details of the underlying phenomenoloy i.e., we now know what happens to exon 1 encoded regions in different concentration regimes with different polyglutamine tracts. We are now building on these findings to develop a mechanistic understanding of how distinct flanking sequences couple differently to polyglutamine tracts in order to engender different mesoscopic and supramolecular behaviors. Our approach is guided by the development of a coarse graining approach that enables the representations of multimolecular assembly proceses at distinct length scales. The choice of resolutions is guided by the physics of block copolymers, the approach to coarse graining is guided by the physics of phase transitions of polymeric systems, and the parameterization method is boostrapped against atomistic simulations is done in force matching methods. The parameters for coarse grain representations are refined using a Gaussian process based Bayesian optimization strategy. We have deployed the multiscale, mutliresolution model to arrive at testable predictions for the different behaviors engendered by the flanking sequences of huntingtin.

Multiscale and multiresolution simulations of aggregation in polyglutamine containing block copolymers

249th National Meeting (2015)

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