Assessment of Disordered Linker Predictions in the CAID2 Experiment

Disordered linkers (DLs) are intrinsically disordered regions that facilitate movement between adjacent functional regions/domains, contributing to many key cellular functions. The recently completed second Critical Assessments of protein Intrinsic Disorder prediction (CAID2) experiment evaluated DL predictions by considering a rather narrow scenario when predicting 40 proteins that are already known to have DLs. We expand this evaluation by using a much larger set of nearly 350 test proteins from CAID2 and by investigating three distinct scenarios: (1) prediction residues in DLs vs. in non-DL regions (typical use of DL predictors); (2) prediction of residues in DLs vs. other disordered residues (to evaluate whether predictors can differentiate residues in DLs from other types of intrinsically disordered residues); and (3) prediction of proteins harboring DLs. We find that several methods provide relatively accurate predictions of DLs in the first scenario. However, only one method, APOD, accurately identifies DLs among other types of disordered residues (scenario 2) and predicts proteins harboring DLs (scenario 3). We also find that APOD's predictive performance is modest, motivating further research into the development of new and more accurate DL predictors. We note that these efforts will benefit from a growing amount of training data and the availability of sophisticated deep network models and emphasize that future methods should provide accurate results across the three scenarios.