LAUSR

It is becoming increasingly recognized that intrinsically disordered proteins are involved in a wide variety of protein interaction modes. In addition to the well-known process of 'folding upon binding' (disorder-to-order transition), many examples of fuzzy complexes are emerging, when the interacting proteins remain to be disordered in the bound state (disorder-to-disorder transitions). Disordered regions may populate ordered and disordered states to different extents depending on the partner ('context-dependent binding'). Here we assemble three datasets comprising disorder-to-order, context-dependent and disorder-to-disorder transitions of 828 protein regions represented in 2157 complexes and elucidate the sequence-determinants of the different interaction modes. We found that fuzzy interactions originate in the lack the local sequence biases in a variety of proteins, which sample a wide range of structure and dynamics. Thus, we have developed the FuzPred method (http://protdyn-fuzpred.org) to predict the different binding modes of disordered proteins based on their amino acid sequence, without specifying their partners. We thus illustrate how the amino acid sequences of proteins can encode a wide range of conformational changes upon binding, including dynamical transitions from disordered to ordered and from disordered to disordered states, resulting in a variety of different interaction modes.