Insights into Self-Assembly Mechanisms of Intrinsically Disordered Proteins from Atomistic Simulations

Intrinsically disordered proteins (IDPs), which lack well­-defined stable structures yet still perform key biological functions, comprise more than one-third of the eukaryotic proteome. Well-ordered fibril structures or aggregation of many IDPs are associated with the pathology of a number of debilitating human diseases including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, type II diabetes, etc. Moreover, certain types of low sequence-complexity IDPs form non-membrane bound intracellular assemblages that co-exist with the cytoplasm showing liquid-like properties, i.e. deform under shear, fuse with one another and take a spherical shape. In this work, we study IDPs, such as TAR DNA-binding protein 43 (TDP-43) or FUsed in Sarcoma (FUS) or Islet Amyloid PolyPeptide (IAPP), forming which are the major constituents of membrane-free assemblages and/or well-ordered pathological aggregates. Structural properties of these IDPs from molecular simulations shed light on intra- and inter-molecular interactions leading self-assembly/aggregation of these proteins.