Disordered Protein Folding and Solubility as a Determinant of Human Disease

A longstanding principle in protein biophysics is that a protein’s sequence dictates its three-dimensional fold, and that structure is inherently linked to function. However, nearly a third of the human proteome contains intrinsically disordered regions that lack a discernible tertiary structure. Many of these proteins, referred to as intrinsically disordered proteins (IDPs), adopt transient conformations in order to carry out a wide-variety of functions, challenging the classical structure-function paradigm. Dysregulation of IDPs can also lead to the pathological accumulation of proteinaceous plaques and fibrils, which are observed in over 22 degenerative diseases and even in many types of cancers. In this talk, I will summarize our efforts to leverage molecular models of IDPs that populate vast free energy landscapes, reconciling how disordered and often soluble protein intermediates contribute to human disease. I will also discuss how these observations can supplement experiments, where transient protein conformations are often extraordinarily difficult to extract.