Intrinsic disorder prediction field develops, assesses, and deploys computational predictors of disorder in protein sequences and constructs and disseminates databases of these predictions. Over 40...

We expand studies of AlphaFold2 (AF2) in the context of intrinsic disorder prediction by comparing it against a broad selection of 20 accurate, popular and recently released disorder predictors. We use 25% larger benchmark dataset with 646 proteins and cover protein-level predictions of disorder content and fully disordered proteins. AF2-based disorder predictions secure a relatively high Area Under receiver operating characteristic Curve (AUC) of 0.77 and are statistically outperformed by several modern disorder predictors that secure AUCs around 0.8 with median runtime of about 20 s compared to 1200 s for AF2. Moreover, AF2 provides modestly accurate predictions of fully disordered proteins (F1 = 0.59 vs. 0.91 for the best disorder predictor) and disorder content (mean absolute error of 0.21 vs. 0.15). AF2 also generates statistically more accurate disorder predictions for about 20% of proteins that have relatively short sequences and a few disordered regions that tend to be located at the sequence termini, and which are absent of disordered protein-binding regions. Interestingly, AF2 and the most accurate disorder predictors rely on deep neural networks, suggesting that these models are useful for protein structure and disorder predictions.

Intrinsically disordered regions (IDRs) carry out many cellular functions and vary in length and placement in protein sequences. This diversity leads to variations in the underlying compositional biases, which were demonstrated for the short vs. long IDRs. We analyze compositional biases across four classes of disorder: fully disordered proteins; short IDRs; long IDRs; and binding IDRs. We identify three distinct biases: for the fully disordered proteins, the short IDRs and the long and binding IDRs combined. We also investigate compositional bias for putative disorder produced by leading disorder predictors and find that it is similar to the bias of the native disorder. Interestingly, the accuracy of disorder predictions across different methods is correlated with the correctness of the compositional bias of their predictions highlighting the importance of the compositional bias. The predictive quality is relatively low for the disorder classes with compositional bias that is the most different from the “generic” disorder bias, while being much higher for the classes with the most similar bias. We discover that different predictors perform best across different classes of disorder. This suggests that no single predictor is universally best and motivates the development of new architectures that combine models that target specific disorder classes.

The DescribePROT database of amino acid-level descriptors of protein structures and functions was substantially expanded since its release in 2020. This expansion includes substantial increase in the size, scope, and quality of the underlying data, the addition of experimental structural information, the inclusion of new data download options, and an upgraded graphical interface. DescribePROT currently covers 19 structural and functional descriptors for proteins in 273 reference proteomes generated by 11 accurate and complementary predictive tools. Users can search our resource in multiple ways, interact with the data using the graphical interface, and download data at various scales including individual proteins, entire proteomes, and whole database. The annotations in DescribePROT are useful for a broad spectrum of studies that include investigations of protein structure and function, development and validation of predictive tools, and to support efforts in understanding molecular underpinnings of diseases and development of therapeutics. DescribePROT can be freely accessed at http://biomine.cs.vcu.edu/servers/DESCRIBEPROT/.

APETALA2/ETHYLENE RESPONSE FACTOR transcription factors (AP2/ERFs) play crucial roles in adaptation to stresses such as those caused by pathogens, wounding and cold. Although their name suggests a specific role in ethylene signalling, some ERF members also co-ordinate signals regulated by other key plant stress hormones such as jasmonate, abscisic acid and salicylate. We analysed a set of ERF proteins from three divergent plant species for intrinsically disorder regions containing conserved segments involved in protein–protein interaction known as Molecular Recognition Features (MoRFs). Then we correlated the MoRFs identified with a number of known functional features where these could be identified. Our analyses suggest that MoRFs, with plasticity in their disordered surroundings, are highly functional and may have been shuffled between related protein families driven by selection. A particularly important role may be played by the alpha helical component of the structured DNA binding domain to permit specificity. We also present examples of computationally identified MoRFs that have no known function and provide a valuable conceptual framework to link both disordered and ordered structural features within this family to diverse function.