Abstract
Huntington's disease is one of nine neurodegenerative diseases characterized by gene mutations causing polyglutamine (polyQ) repeats in various proteins. Mutated proteins misfold, aggregate, and form amyloid-like fibrils in the neuron. As of now, the aggregation mechanism of these polyglutamine proteins is not well understood. Experimental techniques such as resonance Raman, circular dichroism, and ssNMR are used to analyze properties of polyglutamine solutions. Computational analysis is used in concert with experiment to allow investigation on the molecular level. In this work, short polyQ peptides are studied using molecular dynamics (MD) methods in order to better understand the mechanics of their aggregation. In prior work, we characterized the monomeric conformational ensemble of D2Q10K2 peptides. Our next step is to investigate dimerization properties of these peptides. Adaptive biasing force paired with MD is used to evaluate the dimerization free energies and conformations of D2Q10K2 peptides. On a larger scale, classical MD is used to evaluate the properties of multiple aggregate conformations, including facially stacked β-sheet and β-hairpin sheet systems. Ψ angle probability distributions will be generated from the resulting aggregate trajectories for comparison with experimental distributions. Results from both projects will be presented.
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