Proteins & Petides
Modeling of Toxic Aggregates
Several neurodegenerative diseases are related to the misfolding and aggregation of specific proteins, for example Alzheimer's disease, Parkinson's disease and Huntington's disease. Each protein is related to one or more unique diseases, but the protein aggregates seem to share a common structure: insoluble fibrils with β-sheets running parallel to the axis (amyloid). Recent advances however indicate that the toxic particles are probably soluble oligomers, either prefibrillar aggregates or unrelated species. Detailed mechanisms of misfolding and structures of toxic aggregates are yet unknown and difficult to discern through experimental methods.
The Daggett lab studies the early stages of the misfolding and aggregation of the disease-related proteins through molecular dynamics simulations under misfolding conditions. We have previously studied Alzheimer's Aβ peptide, Huntington's polyQ repeats, transthyretin, lysozyme, and β2-microglobulin. Currently, we mostly focus on superoxide dismutase (SOD1) -- related to Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's Disease. We also perform extensive studies on the Prion protein, which is related to several misfolding diseases.
Our studies on SOD1 first focused on one of the most common heritable ALS mutations, a change from alanine to valine at the fourth amino acid (A4V). Simulations indicated that introduction of this mutation causes a loss of residue contacts resulting in destabilization of the dimer and metal-binding sites and a gain of residue contacts that lead to misfolding. Based on this research we have expanded our simulations to other ALS-associated mutations in order to find common features of the mutant forms that may increase their propensity for aggregation.
The knowledge gained on the mechanisms of misfolding and aggregation can be exploited to design markers and inhibitors for disease, another area of active reasearch in the lab.
- Armen R.S., DeMarco M.L., Alonso D.O.V., and Daggett V. Pauling and Corey's α-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease, Proceedings of the National Academy of Sciences USA 101: 11622-11627, 2004. [DOI]
- Armen R.S., Alonso D.O.V., and Daggett V. Anatomy of an amyloidogenic intermediate: Conversion of β-sheet to α-pleated sheet structure in transthyretin at acidic pH, Structure 12: 1847-1863, 2004. [DOI]
- Armen R.S. and Daggett V. Characterization of Two Distinct β2-Microglobulin Unfolding Intermediates that May Lead to Amyloid Fibrils of Different Morphology. Biochemistry 44: 16098-16107, 2005. [DOI]
- Schmidlin T., Kennedy B., and Daggett V. Structural changes to monomeric CuZn Superoxide Dismutase caused by the familial Amyotrophic Lateral Sclerosis mutation A4V. Biophysical Journal 97: 1709-1718, 2009. [DOI]