Probing the dynamics of disorder

Intrinsically disordered proteins (IDPs) play an important role in many diseases. IDPs are a large and important class of proteins; estimated to represent a significant fraction of many genomes. In contrast to protein-protein interactions between well-folded proteins, IDPs typically bind to targets using short consecutive stretches of amino acids. Structures of IDPs complexed with a target have shown great diversity in binding modes. However, how this binding diversity is achieved at the molecular level is not well understood. Unfortunately, the prediction and detailed characterization of IDPs experimentally is still a very challenging task; however molecular mechanics based molecular dynamics simulation are well suited for studying the dynamic behavior of IDPs. We look into the current state for force fields for simulating IDPs and an example of how these methods have been applied to the p53 protein. p53 is one of the most extensively studied IDPs, with multiple intrinsically disordered regulatory domains that mediate its interactions with many other proteins engaged in multiple biological pathways. We show how molecular dynamics simulations can be used to elucidate on the mechanisms involved in selection of the different binding partners.