(117f) Thermodynamics of Misfolding of Polyglutamine Peptides

Huntington’s disease is one of nine inherited neurodegenerative diseases associated with the expansion of a polyglutamine repeat in a disease-specific protein. In each case, disease symptoms appear only if the polyglutamine expansion exceeds a certain threshold length; in Huntington’s disease, the threshold is approximately 36 residues. A hallmark of the expanded polyglutamine diseases is the formation of amyloid fibers rich in aggregated polyglutamine in certain regions of the brain. It has long been thought that the expansion of polyglutamine beyond the threshold length enables the formation of a metastable, misfolded conformer that nucleates aggregation. In this work, we calculate the free energies of different conformers of polyglutamine of lengths spanning the pathological threshold. We employ atomistic molecular dynamics simulations in explicit water to furnish results suitable for direct comparison to in vitro spectroscopic experiments. The results provide insight into the nature of the length dependence of polyglutamine misfolding and aggregation.