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1. Critical assessment of protein intrinsic disorder prediction

   https://doi.org/10.1038/s41592-021-01117-3  

   Necci, Marco; Piovesan, Damiano; Tosatto, Silvio C. (May 2021, Nature Methods)

   null (Ed.)

   Abstract Intrinsically disordered proteins, defying the traditional protein structure–function paradigm, are a challenge to study experimentally. Because a large part of our knowledge rests on computational predictions, it is crucial that their accuracy is high. The Critical Assessment of protein Intrinsic Disorder prediction (CAID) experiment was established as a community-based blind test to determine the state of the art in prediction of intrinsically disordered regions and the subset of residues involved in binding. A total of 43 methods were evaluated on a dataset of 646 proteins from DisProt. The best methods use deep learning techniques and notably outperform physicochemical methods. The top disorder predictor has F max  = 0.483 on the full dataset and F max  = 0.792 following filtering out of bona fide structured regions. Disordered binding regions remain hard to predict, with F max  = 0.231. Interestingly, computing times among methods can vary by up to four orders of magnitude. 

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2. Overview Update: Computational Prediction of Intrinsic Disorder in Proteins

   https://doi.org/10.1002/cpz1.802  

   Uversky, Vladimir N.; Kurgan, Lukasz (June 2023, Current Protocols)

   Abstract There are over 100 computational predictors of intrinsic disorder. These methods predict amino acid‐level propensities for disorder directly from protein sequences. The propensities can be used to annotate putative disordered residues and regions. This unit provides a practical and holistic introduction to the sequence‐based intrinsic disorder prediction. We define intrinsic disorder, explain the format of computational prediction of disorder, and identify and describe several accurate predictors. We also introduce recently released databases of intrinsic disorder predictions and use an illustrative example to provide insights into how predictions should be interpreted and combined. Lastly, we summarize key experimental methods that can be used to validate computational predictions. © 2023 Wiley Periodicals LLC. 

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3. Biophysical and Integrative Characterization of Protein Intrinsic Disorder as a Prime Target for Drug Discovery

   https://doi.org/10.3390/biom13030530  

   Luo, Shuqi; Wohl, Samuel; Zheng, Wenwei; Yang, Sichun (March 2023, Biomolecules)

   Protein intrinsic disorder is increasingly recognized for its biological and disease-driven functions. However, it represents significant challenges for biophysical studies due to its high conformational flexibility. In addressing these challenges, we highlight the complementary and distinct capabilities of a range of experimental and computational methods and further describe integrative strategies available for combining these techniques. Integrative biophysics methods provide valuable insights into the sequence–structure–function relationship of disordered proteins, setting the stage for protein intrinsic disorder to become a promising target for drug discovery. Finally, we briefly summarize recent advances in the development of new small molecule inhibitors targeting the disordered N-terminal domains of three vital transcription factors. 

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4. CLIP: accurate prediction of disordered linear interacting peptides from protein sequences using co-evolutionary information

   https://doi.org/10.1093/bib/bbac502  

   Peng, Zhenling; Li, Zixia; Meng, Qiaozhen; Zhao, Bi; Kurgan, Lukasz (December 2022, Briefings in Bioinformatics)

   Abstract One of key features of intrinsically disordered regions (IDRs) is facilitation of protein–protein and protein–nucleic acids interactions. These disordered binding regions include molecular recognition features (MoRFs), short linear motifs (SLiMs) and longer binding domains. Vast majority of current predictors of disordered binding regions target MoRFs, with a handful of methods that predict SLiMs and disordered protein-binding domains. A new and broader class of disordered binding regions, linear interacting peptides (LIPs), was introduced recently and applied in the MobiDB resource. LIPs are segments in protein sequences that undergo disorder-to-order transition upon binding to a protein or a nucleic acid, and they cover MoRFs, SLiMs and disordered protein-binding domains. Although current predictors of MoRFs and disordered protein-binding regions could be used to identify some LIPs, there are no dedicated sequence-based predictors of LIPs. To this end, we introduce CLIP, a new predictor of LIPs that utilizes robust logistic regression model to combine three complementary types of inputs: co-evolutionary information derived from multiple sequence alignments, physicochemical profiles and disorder predictions. Ablation analysis suggests that the co-evolutionary information is particularly useful for this prediction and that combining the three inputs provides substantial improvements when compared to using these inputs individually. Comparative empirical assessments using low-similarity test datasets reveal that CLIP secures area under receiver operating characteristic curve (AUC) of 0.8 and substantially improves over the results produced by the closest current tools that predict MoRFs and disordered protein-binding regions. The webserver of CLIP is freely available at http://biomine.cs.vcu.edu/servers/CLIP/ and the standalone code can be downloaded from http://yanglab.qd.sdu.edu.cn/download/CLIP/. 

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5. Assessment of Disordered Linker Predictions in the CAID2 Experiment

   https://doi.org/10.3390/biom14030287  

   Wang, Kui; Hu, Gang; Wu, Zhonghua; Uversky, Vladimir N; Kurgan, Lukasz (March 2024, Biomolecules)

   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. 

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