Computational Prediction of MoRFs, Short Disorder-to-order Transitioning Protein Binding Regions

Molecular recognition features (MoRFs) are short protein-binding regions that undergo disorder-to-order transitions (induced folding) upon binding protein partners. These regions are abundant in nature and can be predicted from protein sequences based on their distinctive sequence signatures. This first-of-its-kind survey covers 14 MoRF predictors and six related methods for the prediction of short protein-binding linear motifs, disordered protein-binding regions and semi-disordered regions. We show that the development of MoRF predictors has accelerated in the recent years. These predictors depend on machine learning-derived models that were generated using training datasets where MoRFs are annotated using putative disorder. Our analysis reveals that they generate accurate predictions. We identified eight methods that offer area under the ROC curve (AUC) ≥ 0.7 on experimentally-validated test datasets. We show that modern MoRF predictors accurately find experimentally annotated MoRFs even though they were trained using the putative disorder annotations. They are relatively highly-cited, particularly the methods available as webservers that on average secure three times more citations than methods without this option. MoRF predictions contribute to the experimental discovery of protein-protein interactions, annotation of protein functions and computational analysis of a variety of proteomes, protein families, and pathways. We outline future development and application directions for these tools, stressing the importance to develop novel tools that would target interactions of disordered regions with other types of partners.