The DOI matches its Crossref record; 97 of the 103 references it cites were found in a registry or an index; 1 of the 58 sources its claims cite were checked for support.
AlphaFold and Implications for Intrinsically Disordered Proteins
Open accessAbstract
Accurate predictions of the three-dimensional structures of proteins from their amino acid sequences have come of age. AlphaFold, a deep learning-based approach to protein structure prediction, shows remarkable success in independent assessments of prediction accuracy. A significant epoch in structural bioinformatics was the structural annotation of over 98% of protein sequences in the human proteome. Interestingly, many predictions feature regions of very low confidence, and these regions largely overlap with intrinsically disordered regions (IDRs). That over 30% of regions within the proteome are disordered is congruent with estimates that have been made over the past two decades, as intense efforts have been undertaken to generalize the structure-function paradigm to include the importance of conformational heterogeneity and dynamics. With structural annotations from AlphaFold in hand, there is the temptation to draw inferences regarding the "structures" of IDRs and their interactomes. Here, we offer a cautionary note regarding the misinterpretations that might ensue and highlight efforts that provide concrete understanding of sequence-ensemble-function relationships of IDRs. This perspective is intended to emphasize the importance of IDRs in sequence-function relationships (SERs) and to highlight how one might go about extracting quantitative SERs to make sense of how IDRs function.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This perspective cautions against over-interpreting AlphaFold’s low-confidence and “unstructured” annotations for intrinsically disordered regions as literal structures or as failures of prediction. It argues that quantitative sequence–ensemble descriptions, not static models, are needed to understand IDR function.
Key findings
- AlphaFold annotated over 98% of human proteome sequences, but roughly 30% of residues have pLDDT scores below 50, consistent with estimates that about 30% of the human proteome is disordered.
- Low-confidence regions largely overlap intrinsically disordered regions (IDRs); the authors argue most are likely genuinely disordered rather than well-folded structures that AlphaFold missed.
- Static AlphaFold structures of IDRs often overestimate radius of gyration relative to SAXS measurements, as shown for p27 CTD and the hnRNP-A1 prion-like low-complexity domain (A1-LCD).
- Quantitative ensembles from atomistic simulations vetted by experiments reveal sequence-specific behavior: p27 CTD behaves on average like a Flory random coil, A1-LCD uses aromatic stickers/spacers, and Httex1 prefers tadpole-like conformations with polyQ radius scaling as n^1/3.
Methods
- Perspective/cautionary note, not primary research; it synthesizes the AlphaFold papers, human proteome annotations, and prior IDP literature.
- Uses illustrative examples—p27 Kip1 CTD, hnRNP-A1 A1-LCD, and huntingtin exon 1 (Httex1)—comparing AlphaFold static structures with SAXS, NMR, smFRET, and atomistic simulations based on the ABSINTH implicit solvation model and forcefield.
- Main analysis is interpretive and qualitative, focused on why static AlphaFold depictions of IDRs lack physical meaning and how sequence–ensemble relationships should instead be quantified.
Limitations
- The paper does not state formal limitations.
- Evident from the text: it is a perspective/opinion piece, not a systematic review, and its examples are drawn largely from the authors’ own work and close colleagues.
- Evident from the text: no new experimental data are reported; the quantitative examples rely on previously published simulations and experiments, and the scope is limited to interpreting AlphaFold annotations for IDRs.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
38 Not checked yet · 9 Own interpretation · 9 No basis given · 5 Own result · 1 Own method · accuracy not yet measured
None of the sources cited for this claim have been checked yet.
In the paper
“Conservative estimates indicate that roughly 30% of sequences, 30residues or longer, drawn at random from the human proteome, are likely to be IDRs. 3,5”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
What the sources say
- Not checked yetcites [3] source
- Could not verifycites [5] sourceExperimental — accuracy not yet measured
The Results describe DisProt annotations and note that the dataset is biased toward model organisms, including humans; they do not estimate the prevalence of IDRs in randomly sampled human-proteome sequences. Searches for a 30% estimate and a 30-residue threshold found no passage supporting those figures. (LLM, conf=0.70)
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In the paper
“Integrating SAXS and NMR measurements with simulations, suggests that the ensemble of conformations fluctuate among locally compact regions, globally compact conformations, and expanded conformations.88”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > The prion-like complexity domain from hnRNPA1
What the sources say
- Not checked yetcites [88] source
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In the paper
“Interestingly, many predictions feature regions of very low confidence, and these regions largely overlap with intrinsically disordered regions (IDRs).”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, the efficiency of T187 phosphorylation does not change monotonically with changes to R g .”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Examples of sequence-ensemble descriptions obtained from atomistic simulations vetted by comparisons to multipronged experiments
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In the paper
“Roughly 30% of the residues across predicted structures in the human proteome tend to have pLDDT scores that are less than 50.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Instead, there is a cryptic motif that is proxi-mal to the primary substrate motif that regulates the efficiency of T187 phosphorylation.64”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Examples of sequence-ensemble descriptions obtained from atomistic simulations vetted by comparisons to multipronged experiments
What the sources say
- Not checked yetcites [64]
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The R g value we compute using the very low confidence static structure excised from the AlphaFold prediction is considerably higher than values obtained from direct measurements based on SAXS (Figure 2(C)).”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > The prion-like complexity domain from hnRNPA1
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In the paper
“These conformational features are driven by the distributed network of contacts formed between pairs of sequenceproximal or distal aromatic residues and influenced or diluted by the spacer regions that are interspersed between aromatic residues (stickers).88”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > The prion-like complexity domain from hnRNPA1
What the sources say
- Not checked yetcites [88] source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The C-terminal domain of p27, p27 CTD , generally shows low pLDDT scores (<70) in the AlphaFold prediction.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Examples of sequence-ensemble descriptions obtained from atomistic simulations vetted by comparisons to multipronged experiments
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This is because, the static AlphaFold structure likely overestimates the radius of gyration of IDRs as measured using small angle X-ray scattering (SAXS) 64 (Figure 2(A)).”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
What the sources say
- Not checked yetcites [64]
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 10
- The quote only partly states this claim. 2
- Probably not a substantial claim. 9
In the paper
“Modulating the charge patterning changes the mean size of the conformational ensemble monotonically, consistent with SAXS experiments.64”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Examples of sequence-ensemble descriptions obtained from atomistic simulations vetted by comparisons to multipronged experiments
What the sources say
- Not checked yetcites [64]
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“A sizable fraction of the N-terminal region is predicted to adopt a helical structure by Alpha-Fold, and this is consistent with experimental characterizations based on nuclear magnetic resonance (NMR) spectroscopy.85”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Examples of sequence-ensemble descriptions obtained from atomistic simulations vetted by comparisons to multipronged experiments
What the sources say
- Not checked yetcites [85]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Atomistic simulations reproduce the average R g value measured using SAXS.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > DECLARATION OF COMPETING INTEREST
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“This ensemble is sequence-specific 30,31 and the extent of heterogeneity 36 as well as the relative preferences of conformations within the ensemble will depend on the primary sequence, solution conditions, and functional contexts.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
What the sources say
- Not checked yetcites [30]
- Not checked yetcites [31]
- Not checked yetcites [36]
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Instead, disorder implies that a diverse conformational ensemble best describes the region of interest.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
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In the paper
“The N-terminal portion (residues 1-95) folds upon binding to Cdk2/cyclin A and this leads to kinase inhibition.85,86”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Examples of sequence-ensemble descriptions obtained from atomistic simulations vetted by comparisons to multipronged experiments
What the sources say
- Not checked yetcites [85]
- Not checked yetcites [86]
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the current dataset, long regions with pLDDT < 50 adopt a readily identifiable ribbon-like appearance, and should not be interpreted as structures but rather as a prediction of disorder.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Intrinsically disordered regions often evolve more rapidly than ordered regions and thus alignments of these regions are generally poorer and involve large gaps and extensions of gaps because orthologous IDRs can span vast sequence lengths.9,23,58,60,[68][69][70]”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
What the sources say
- Not checked yetcites 9,23,58,60,[68][69][70]
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Alleviation of steric clashes leads to a steep decrease in the potential energy, and often the local minimum will be situated closest to the region of the steepest drop in energy.72,73”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
What the sources say
- Not checked yetcites [72]
- Not checked yetcites [73]
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Over the past two decades, there has been growing recognition that the sequence-structurefunction paradigm must be generalized to account for the role of conformational heterogeneity and conformational dynamics in protein function.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“created quite a stir when it was deployed to predict the structures of 98.5% of proteins in the human proteome.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“leading to the postulate, tested through theory, computations, and experiments, that aromatic residues function as cohesive motifs known as stickers that drive single chain compaction as well as phase separation 88 -the latter through a network of intermolecular interactions.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > The prion-like complexity domain from hnRNPA1
What the sources say
- Not checked yetcites [88]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Under standard conditions used to study and characterize protein structures, IDPs/IDRs are defined by conformational heterogeneity, and the preference for heterogeneity is encoded in their amino acid sequences.11,[29][30][31]”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
What the sources say
- Not checked yetcites [11]
- Not checked yetcites [29]
- Not checked yetcites [30]
- Not checked yetcites [31]
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The overall number of distinct conformations in the ensemble, the conformational heterogeneity, in terms of features such as the sizes and shapes sampled, and the relative importance of different conformations within the ensemble are defined by a combination of sequence-encoded short-and long-range interactions 37,38 as well as the modulation of these interactions by solution conditions.39,40”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
What the sources say
- Not checked yetcites [37]
- Not checked yetcites [38]
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- Not checked yetcites [40]
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Importantly, prediction engines are also available to identify regions that undergo disorder-to-order, order-to-disorder, and disorder-to-disorder transitions upon binding.44”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
What the sources say
- Not checked yetcites [44]
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The Pro-rich C-terminal region forms a semi-flexible tail.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Conformational ensembles of the exon 1 encoded region of huntingtin (Httex1)
What the sources say
- Not checked yetcites [94]
plain- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
In the paper
“IDPs/IDRs are best defined by a heterogeneous ensemble of conformations.36”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Introduction
What the sources say
- Not checked yetcites [36]
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“Taken together with complementary efforts focused on characterizing Httex1 phase behavior, the results obtained from multipronged studies of monomeric Httex1 predict that the growth of the “sticky head” with polyQ length mediates homotypic interactions and modulates heterotypic interactions in the cellular context.94”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > Conformational ensembles of the exon 1 encoded region of huntingtin (Httex1)
What the sources say
- Not checked yetcites [94]
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“Evidence in favor of this point of view is the successful prediction of natively disordered protein regions by AlphaFold and the correlation between the decrease of pLDDT and propensity to be in a disordered region [25].”
From Using AlphaFold to predict the impact of single mutations on protein stability and function (2023) · cites this paper as [25]
In the citing paper
“like peptides, IDPs and IDRs are best thought of as sampling diverse conformational ensembles rather than a single static conformation42”
From The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins (2024) · cites this paper as [42]
In the citing paper
“Ruff et al showed that radius of gyration values of IDPs / IDR containing proteins calculated using static AF2 models significantly deviates from those experimentally obtained by small-angle X-ray scattering (SAXS)42”
From The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins (2024) · cites this paper as [42]
In the citing paper
“Preliminary studies suggest that the majority of targets with very low-confidence score (pLDDT < 50) assigned by AF2 are likely to be IDPs / IDRs rather than well-folded structures that AF2 fails to predict42–44”
From The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins (2024) · cites this paper as [42]
In the citing paper
“Some groups have used MD simulations to suggest that pLDDT and PAE metrics provide information on dynamics and disorder42,65”
From The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins (2024) · cites this paper as [42]
In the citing paper
“Preliminary comparison of SAXS-derived versus AF calculated P(r) curves revealed that for many cases a static AF2 model does not adequately describe solution state structures42,72.”
From The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins (2024) · cites this paper as [42]
In the citing paper
“It is therefore not surprising that it was recently shown [214] that data-driven approaches can hardly predict the structure of so-called intrinsically disordered proteins”
From Quantum Computing for Molecular Biology** (2023) · cites this paper as [214]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ AlphaFold and Implications for Intrinsically Disordered Proteins > References
“26. Miskei, M., Antal, C., Fuxreiter, M., (2016). FuzDB: database of fuzzy complexes, a tool to develop stochastic structure-function relationships for protein complexes and higher-order assemblies. Nucleic Acids Res., 45, D228- D235.”
§ AlphaFold and Implications for Intrinsically Disordered Proteins > References
“26. To ´th-Petro ´czy, A ´., Oldfield, C.J., Simon, I., Takagi, Y., Dunker, A.K., Uversky, V.N., et al., (2008). Malleable machines in transcription regulation: The mediator complex. PLoS Comput. Biol., 4, e1000243”
Citations
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Highly accurate protein structure prediction for the human proteome
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Valence and patterning of aromatic residues determine the phase behavior of prion-like domains
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Self-citation
Cited by
Sorted by citations
The molecular basis for cellular function of intrinsically disordered protein regions
Holehouse, A. S., & Kragelund, B. B. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00673-0 · Cited by 741
Conformational ensembles of the human intrinsically disordered proteome
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“When methods such as AlphaFold are applied to IDRs, however, they result in a single configuration or few configurations of low confidence, which do not represent the conformational heterogeneity and functional states of IDRs 6 .”
Before and after AlphaFold2: An overview of protein structure prediction
Bertoline, L. M. F., Lima, A. N., Krieger, J. E., & Teixeira, S. K. (2023) · Frontiers in Bioinformatics · doi:10.3389/fbinf.2023.1120370 · Cited by 330
“Ruff and Pappu (2021) demonstrated that residues and regions predicted with low accuracy by AlphaFold2 overlaps intrinsically disordered regions, while Stevens and He (2022) showed that only short loops ( 20 amino acids) are predicted with high accuracy by AlphaFold and it has the tendency to…”
BackgroundUsing AlphaFold to predict the impact of single mutations on protein stability and function
Pak, M. A., Markhieva, K. A., Novikova, M. S., Petrov, D. S., Vorobyev, I. S., Maksimova, E. S., Kondrashov, F. A., & Ivankov, D. N. (2023) · PLOS One · doi:10.1371/journal.pone.0282689 · Cited by 322
“Evidence in favor of this point of view is the successful prediction of natively disordered protein regions by AlphaFold and the correlation between the decrease of pLDDT and propensity to be in a disordered region [25].”
BackgroundThe AlphaFold Database of Protein Structures: A Biologist’s Guide
David, A., Islam, S., Tankhilevich, E., & Sternberg, M. J. E. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167336 · Cited by 268
Metadata
- Authors
- Ruff, K. M., & Pappu, R. V.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Pappu, Rohit V.
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 433
- Issue
- 20
- Pages
- 167208
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W3195375135
- Semantic Scholar
- 960aaaa85d1de9f8e2490d872165b720e3d4b565
- Cited by
- 635
- References
- 103
- Citations by year
- 2026: 97 · 2025: 154 · 2024: 139 · 2023: 144 · 2022: 91 · 2021: 10
- FWCI
- 10.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Molecular Biology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- AlphaFold, intrinsically disordered regions, protein structure prediction, sequence-function relationships, conformational heterogeneity, protein dynamics, protein-protein interaction network
- MeSH terms
- Deep Learning, Animals, Humans, Models, Molecular, Protein Conformation, Protein Folding, Computational Biology, Proteome, Intrinsically Disordered Proteins
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