Sequence-based prediction of protein binding mode landscapes

Interactions between disordered proteins involve a wide range of changes in the structure and dynamics of the partners involved. These changes can be classified in terms of binding modes, which include disorder-to-order (DO) transitions, when proteins fold upon binding, as well as disorder-to-disorder (DD) transitions, when the conformational heterogeneity is maintained in the bound states. Furthermore, systematic studies of these interactions are revealing that proteins may exhibit different binding modes with different partners. Proteins that exhibit this context-dependent binding can be referred to as fuzzy proteins. Here we investigate amino acid code for fuzzy binding in terms of the Shannon entropy of the probabilities of transitions towards increasing or decreasing order (p(DO) and p(DD)). We implement these entropy calculations into the FuzPred (http://protdyn-fuzpred.org) algorithm to predict the range of context-dependent binding modes of proteins from their amino acid sequences. As we illustrate through a variety of examples, this method identifies those binding sites that are sensitive to the cellular context or post-translational modifications, and may serve as regulatory points of cellular pathways. Author summary Great advances have been made in the last several decades in deciphering how the behavior of proteins is encoded in their amino acid sequences. A variety of sequence-based prediction methods have been developed to estimate a wide range of properties of proteins, including secondary structure propensity, native state structures, preference for being disordered and tendency to aggregate. Much less is known, however, about the rules that regulate the conformational changes of proteins upon interacting with their functional partners. In particular, many proteins change their binding modes upon interacting with different partners, or as a consequence of post-translational modifications or changes in the cellular milieu. Here we address the problem of how amino acid sequences can encode different binding modes depending on their binding partners, and describe the FuzPred method of predicting context-dependent binding modes.