Intrinsically disorder regions (IDRs) are abundant in nature, particularly among Eukaryotes. While they facilitate a wide spectrum of cellular functions including signaling, molecular assembly and recognition, translation, transcription and regulation, only several hundred IDRs are annotated functionally. This annotation gap motivates the development of fast and accurate computational methods that predict IDR functions directly from protein sequences. We introduce and describe a comprehensive collection of 25 methods that provide accurate predictions of IDRs that interact with proteins and nucleic acids, that function as flexible linkers and that moonlight multiple functions. Virtually all of these predictors can be accessed online and many were developed in the last few years. They utilize a wide range of predictive architectures and take advantage of modern machine learning algorithms. Our empirical analysis shows that predictors that are available as webservers enjoy high rates of citations, attesting to their practical value and popularity. The most cited methods include DISOPRED3, ANCHOR, alpha-MoRFpred, MoRFpred, fMoRFpred and MoRFCHiBi. We present two case studies to demonstrate that predictions produced by these computational tools are relatively easy to interpret and that they deliver valuable functional clues. However, the current computational tools cover a relatively narrow range of disorder functions. Further development efforts that would cover a broader range of functions should be pursued. We demonstrate that a sufficient amount of functionally annotated IDRs that are associated with several other disorder functions is already available and can be used to design and validate novel predictors.
Keywords: DNA binding; Flexible linker; Intrinsic disorder; Intrinsic disorder functions; Intrinsically disordered regions; Moonlighting; Prediction; Protein binding; RNA binding.
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