ArticleProceedings of the National Academy of Sciences of the United States of America2023
Systematic identification of conditionally folded intrinsically disordered regions by AlphaFold2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers.
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130 citing papers in PubMed, 208 citations in OpenAlex.
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- Intermolecular β-sheet Formation Guides the Interaction between Ubiquitin-like Modifier FAT10 and Adapter Protein NUB1L.Journal of the American Chemical Society · 2026Article
- Limitations of the refolding pipeline for de novo protein design.Protein science : a publication of the Protein Society · 2026Article
- Functional flexibility in bacterial hub proteins is driven by proteome expansion.Scientific reports · 2026Article
- Optimized optogenetic anti-CRISPR for endogenous gene regulation in Drosophila.Nucleic acids research · 2026Article
- SSAS-GO: structure-sequence adaptive synergy network for protein function prediction.Briefings in bioinformatics · 2026Article
- Uncovering viral protein acquisition events and human-specific folds with pairwise comparisons of predicted protein structures.Molecular biology and evolution · 2026Article
- Structural mechanism for noncanonical GPCR signaling in the Hedgehog pathway.Nature structural & molecular biology · 2026Article
- Molecular Modeling of the Pathogenetic Mechanisms of Neuropsychiatric Disorders.International journal of molecular sciences · 2026Review
- Evaluation of Cleavable Crosslinking for Characterization of Proteoform Structural Differences by Top-Down Mass Spectrometry.International journal of mass spectrometry · 2026Article
- Accurate conformational ensembles of intrinsically disordered proteins using reweighting based on NMR chemical shifts.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Allostery in Biomolecular Condensates.Journal of molecular biology · 2026Review
- Article
- Atomic resolution ensembles of intrinsically disordered proteins with Alphafold.Nature communications · 2026Article
70 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
The AlphaFold Protein Structure Database contains predicted structures for millions of proteins. For the majority of human proteins that contain intrinsically disordered regions (IDRs), which do not adopt a stable structure, it is generally assumed that these regions have low AlphaFold2 confidence scores that reflect low-confidence structural predictions. Here, we show that AlphaFold2 assigns confident structures to nearly 15% of human IDRs. By comparison to experimental NMR data for a subset of IDRs that are known to conditionally fold (i.e., upon binding or under other specific conditions), we find that AlphaFold2 often predicts the structure of the conditionally folded state. Based on databases of IDRs that are known to conditionally fold, we estimate that AlphaFold2 can identify conditionally folding IDRs at a precision as high as 88% at a 10% false positive rate, which is remarkable considering that conditionally folded IDR structures were minimally represented in its training data. We find that human disease mutations are nearly fivefold enriched in conditionally folded IDRs over IDRs in general and that up to 80% of IDRs in prokaryotes are predicted to conditionally fold, compared to less than 20% of eukaryotic IDRs. These results indicate that a large majority of IDRs in the proteomes of human and other eukaryotes function in the absence of conditional folding, but the regions that do acquire folds are more sensitive to mutations. We emphasize that the AlphaFold2 predictions do not reveal functionally relevant structural plasticity within IDRs and cannot offer realistic ensemble representations of conditionally folded IDRs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.