Towards the physical basis of how intrinsic disorder mediates protein function

► Physical basis of intrinsic disorder for function remains to be established. ► Detailed characterization of dynamic conformational ensembles of IDPs is necessary. ► Integrated computational and experimental strategies are the most effective. ► Induced folding-like mechanisms appear to be prevalent in IDP recognition. ► Efficient folding upon encounter is required for fast IDP association kinetics. Intrinsically disordered proteins (IDPs) are an important class of functional proteins that is highly prevalent in biology and has broad association with human diseases. In contrast to structured proteins, free IDPs exist as heterogeneous and dynamical conformational ensembles under physiological conditions. Many concepts have been discussed on how such intrinsic disorder may provide crucial functional advantages, particularly in cellular signaling and regulation. Establishing the physical basis of these proposed phenomena requires not only detailed characterization of the disordered conformational ensembles, but also mechanistic understanding of the roles of various ensemble properties in IDP interaction and regulation. Here, we review the experimental and computational approaches that may be integrated to address many important challenges of establishing a “structural” basis of IDP function, and discuss some of the key emerging ideas on how the conformational ensembles of IDPs may mediate function, especially in coupled binding and folding interactions.