Intrinsically disordered proteins are proteins that lack a stable three dimensional structure. In many cases they control vital cellular processes or have been associated with disease. In this project, we use computer simulations to study a protein called IAPP that clumps up harmfully in type 2 diabetes, killing the cells that make insulin. Lacking fixed structure, IAPP's flexible conformations shift with mutations toward fibril-prone states that block insulin from working properly. Our simulations will reveal how these mutations propagate disruptive dynamics along the chain, identifying "switches" for aggregation. This will guide drug discovery by predicting stabilizers that restore soluble, functional ensembles or inhibitors blocking toxic fibrils— targets beyond conventional pockets.

(Computational)