CoChat
Sign Up
Cited by 1,144Protein Structure and DynamicsEnzyme Structure and FunctionRNA and protein synthesis mechanisms

The DOI matches its Crossref record; 83 of the 84 references it cites were found in a registry or an index.

Protein 3D Structure Computed from Evolutionary Sequence Variation

Open access
Marks, Debora S., Colwell, Lucy J., Sheridan, Robert, Hopf, Thomas A., Pagnani, Andrea, Zecchina, Riccardo, Sander, Chris·2011·PLoS ONE
DOI 10.1371/journal.pone.0028766PMC PMC3233603
Open this paper in CoChat — free accountOpen PDF

Abstract

The evolutionary trajectory of a protein through sequence space is constrained by its function. Collections of sequence homologs record the outcomes of millions of evolutionary experiments in which the protein evolves according to these constraints. Deciphering the evolutionary record held in these sequences and exploiting it for predictive and engineering purposes presents a formidable challenge. The potential benefit of solving this challenge is amplified by the advent of inexpensive high-throughput genomic sequencing.In this paper we ask whether we can infer evolutionary constraints from a set of sequence homologs of a protein. The challenge is to distinguish true co-evolution couplings from the noisy set of observed correlations. We address this challenge using a maximum entropy model of the protein sequence, constrained by the statistics of the multiple sequence alignment, to infer residue pair couplings. Surprisingly, we find that the strength of these inferred couplings is an excellent predictor of residue-residue proximity in folded structures. Indeed, the top-scoring residue couplings are sufficiently accurate and well-distributed to define the 3D protein fold with remarkable accuracy.We quantify this observation by computing, from sequence alone, all-atom 3D structures of fifteen test proteins from different fold classes, ranging in size from 50 to 260 residues, including a G-protein coupled receptor. These blinded inferences are de novo, i.e., they do not use homology modeling or sequence-similar fragments from known structures. The co-evolution signals provide sufficient information to determine accurate 3D protein structure to 2.7-4.8 Å C(α)-RMSD error relative to the observed structure, over at least two-thirds of the protein (method called EVfold, details at http://EVfold.org). This discovery provides insight into essential interactions constraining protein evolution and will facilitate a comprehensive survey of the universe of protein structures, new strategies in protein and drug design, and the identification of functional genetic variants in normal and disease genomes.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0028766

Cites

83 of 83 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Correlated mutations carry information about distance relationships in protein structure. The sequence of the protein for which the 3D structure is to be predicted (each circle is an amino acid residue, typical sequence length is 50–250 residues) is part of an evolutionarily related family of sequences (amino acid residue types in standard one-letter code) that are presumed to have essentially the same fold (iso-structural family). Evolutionary variation in the sequences is constrained by a number of requirements, including the maintenance of favorable interactions in direct residue-residue contacts (red line, right). The inverse problem of protein fold prediction from sequence addressed here exploits pair correlations in the multiple sequence alignment (left) to deduce which residue pairs are likely to be close to each other in the three-dimensional structure (right). A subset of the predicted residue contact pairs is subsequently used to fold up any protein in the family into an approximate predicted 3D shape (‘fold’) which is then refined using standard molecular physics techniques, yielding a predicted all-atom 3D structure of the protein of interest.
Figure 1 Correlated mutations carry information about distance relationships in protein structure. The sequence of the protein for which the 3D structure is to be predicted (each circle is an amino acid residue, typical sequence length is 50–250 residues) is part of an evolutionarily related family of sequences (amino acid residue types in standard one-letter code) that are presumed to have essentially the same fold (iso-structural family). Evolutionary variation in the sequences is constrained by a number of requirements, including the maintenance of favorable interactions in direct residue-residue contacts (red line, right). The inverse problem of protein fold prediction from sequence addressed here exploits pair correlations in the multiple sequence alignment (left) to deduce which residue pairs are likely to be close to each other in the three-dimensional structure (right). A subset of the predicted residue contact pairs is subsequently used to fold up any protein in the family into an approximate predicted 3D shape (‘fold’) which is then refined using standard molecular physics techniques, yielding a predicted all-atom 3D structure of the protein of interest.CC BY · PubMed Central
Figure 2 Predicted 3D structures for three representative proteins. Visual comparison of 3 of the 15 test proteins (others in Figure S3) reveals the remarkable agreement of the predicted top ranked 3D structure (left) and the experimentally observed structure (right). Center: Cα-RMSD error and, in parentheses, number of residues used for Cα-RMSD error calculation, e.g., 2.9 Å Cα-RMSD (67). The ribbon representation was chosen to highlight the overall topographical progression of the polypeptide chain, rather than atomic details such as hydrogen bonding (colored blue to red in rainbow colors along the chain, N-term to C-term; helical ribbons are α-helices, straight ribbons are β-strands, arrow in the direction of the chain; each structure in front and back view, related by 180 degree rotation). The predicted proteins can be viewed in full atomic detail in deposited graphics sessions for the Pymol program (Web Appendix A4) or from their coordinates (Web Appendix A).
Figure 2 Predicted 3D structures for three representative proteins. Visual comparison of 3 of the 15 test proteins (others in Figure S3) reveals the remarkable agreement of the predicted top ranked 3D structure (left) and the experimentally observed structure (right). Center: Cα-RMSD error and, in parentheses, number of residues used for Cα-RMSD error calculation, e.g., 2.9 Å Cα-RMSD (67). The ribbon representation was chosen to highlight the overall topographical progression of the polypeptide chain, rather than atomic details such as hydrogen bonding (colored blue to red in rainbow colors along the chain, N-term to C-term; helical ribbons are α-helices, straight ribbons are β-strands, arrow in the direction of the chain; each structure in front and back view, related by 180 degree rotation). The predicted proteins can be viewed in full atomic detail in deposited graphics sessions for the Pymol program (Web Appendix A4) or from their coordinates (Web Appendix A).CC BY · PubMed Central
Figure 3 Progress in contact prediction using the maximum entropy method. Extraction of evolutionary information about residue coupling and predicted contacts from multiple sequence alignments works much better using the global statistical model (right, Direct Information, DI, Equation 3) than the local statistical model (left, Mutual Information, MI, Equation 1). Predicted contacts for DI (red lines connecting the residues predicted to be coupled from sequence information) are better positioned in the experimentally observed structure (grey ribbon diagram), than those for MI (left, blue lines), shown here for the RAS protein (upper) and ELAV4 protein (lower). The DI residue pairs are also more evenly distributed along the chain and overlap more accurately with the contacts in the observed structure (red stars [predicted, grey circles [observed] in contact map; center, upper right triangle) than those using MI (blue [predicted], grey circles [observed]; center, lower left triangle). Details of contact maps for all proteins comparing predicted and observed contacts are in Figures S1 and S2, Text S1.
Figure 3 Progress in contact prediction using the maximum entropy method. Extraction of evolutionary information about residue coupling and predicted contacts from multiple sequence alignments works much better using the global statistical model (right, Direct Information, DI, Equation 3) than the local statistical model (left, Mutual Information, MI, Equation 1). Predicted contacts for DI (red lines connecting the residues predicted to be coupled from sequence information) are better positioned in the experimentally observed structure (grey ribbon diagram), than those for MI (left, blue lines), shown here for the RAS protein (upper) and ELAV4 protein (lower). The DI residue pairs are also more evenly distributed along the chain and overlap more accurately with the contacts in the observed structure (red stars [predicted, grey circles [observed] in contact map; center, upper right triangle) than those using MI (blue [predicted], grey circles [observed]; center, lower left triangle). Details of contact maps for all proteins comparing predicted and observed contacts are in Figures S1 and S2, Text S1.CC BY · PubMed Central
Figure 4 Accuracy of blinded 3D structure inference. A. The overall performance of the de novo structure prediction reported here based on contacts inferred from evolutionary information (EICs), ranges from good to excellent for the 15 test proteins (on left: 3D structure type [α = α-helix-containing, β = β-strand-containing, 7tm-α = containing seven trans-membrane helices]; in parentheses: size of protein domain/number of residues used for Cα-RMSD error calculation; on bar: Uniprot database ID). Larger bars mean better performance, i.e., lower Cα-RMSD co-ordinate error. Left: performance for the top ranked structure for each target protein out of 400–560 (depending on the size of the protein, 20 structures per NC bin, NC in steps of 10, details in Appendix A3 and A6) candidate structures in blind prediction mode; right: performance of the best structure, in hindsight, out of 20 candidate structures generated, for 20 sets of constraints ranging from 10∶200, in steps of 10. This reflects what would be achievable with better ranking criteria or independent post-prediction validation of structure quality (Table 1; details of blind ranking scores in Web Appendix A5). Other well-accepted methods for error assessment, such as GDT-TS and TM score are useful for comparison purposes (Table S1, Web Appendix A6). B. Ranking score of each candidate structure (quantifying expected structure quality) versus Cα-RMSD error. Ideally, higher-ranking scores correspond to lower error. The distribution of the candidate structures (black dots) for Elav4, Ras and Trypsin shows, in retrospect, that the ranking criteria used here are relatively useful and help in anticipating which structures are likely to be best (plots for all tested proteins in Figure S5). In blind prediction mode, a list of predicted candidate 3D structure has to be ranked by objective and automated criteria, with a single top ranked structure or a set of top ranked structures nominated as preferred predictions.
Figure 4 Accuracy of blinded 3D structure inference. A. The overall performance of the de novo structure prediction reported here based on contacts inferred from evolutionary information (EICs), ranges from good to excellent for the 15 test proteins (on left: 3D structure type [α = α-helix-containing, β = β-strand-containing, 7tm-α = containing seven trans-membrane helices]; in parentheses: size of protein domain/number of residues used for Cα-RMSD error calculation; on bar: Uniprot database ID). Larger bars mean better performance, i.e., lower Cα-RMSD co-ordinate error. Left: performance for the top ranked structure for each target protein out of 400–560 (depending on the size of the protein, 20 structures per NC bin, NC in steps of 10, details in Appendix A3 and A6) candidate structures in blind prediction mode; right: performance of the best structure, in hindsight, out of 20 candidate structures generated, for 20 sets of constraints ranging from 10∶200, in steps of 10. This reflects what would be achievable with better ranking criteria or independent post-prediction validation of structure quality (Table 1; details of blind ranking scores in Web Appendix A5). Other well-accepted methods for error assessment, such as GDT-TS and TM score are useful for comparison purposes (Table S1, Web Appendix A6). B. Ranking score of each candidate structure (quantifying expected structure quality) versus Cα-RMSD error. Ideally, higher-ranking scores correspond to lower error. The distribution of the candidate structures (black dots) for Elav4, Ras and Trypsin shows, in retrospect, that the ranking criteria used here are relatively useful and help in anticipating which structures are likely to be best (plots for all tested proteins in Figure S5). In blind prediction mode, a list of predicted candidate 3D structure has to be ranked by objective and automated criteria, with a single top ranked structure or a set of top ranked structures nominated as preferred predictions.CC BY · PubMed Central
Figure 5 Top-ranked predicted structures can make correct contacts in the absence of constraints and avoid incorrect contacts in spite of false positive constraints. The top blindly ranked structures are evaluated in terms of quality of contact prediction (NC = 40 for Elav4, NC = 130 for Ras, NC = 160 for Trypsin). The predicted constraints (red stars) are correct when they coincide with contacts derived from the observed structure (grey circles) and otherwise incorrect (false positives, red on white). The contacts derived from the predicted 3D structure (dark blue) are in good general agreement with those from the observed structure (grey). The cooperative nature of the folding prediction process permits favorable situations, in which contacts regions not touched by a predicted constraint (red) are still predicted correctly (black circle for RAS, dark blue on grey, no red) and false positive constraints are not strong enough to lead to incorrect contacts (left black circle Elav4, red star, no dark blue or grey). However, in unfavorable situations missing constraints may imply that contact regions are fully or partially missed (black circle, trypsin) or mostly missed (right black circle for Elav4, grey adjacent to and wider than dark blue).
Figure 5 Top-ranked predicted structures can make correct contacts in the absence of constraints and avoid incorrect contacts in spite of false positive constraints. The top blindly ranked structures are evaluated in terms of quality of contact prediction (NC = 40 for Elav4, NC = 130 for Ras, NC = 160 for Trypsin). The predicted constraints (red stars) are correct when they coincide with contacts derived from the observed structure (grey circles) and otherwise incorrect (false positives, red on white). The contacts derived from the predicted 3D structure (dark blue) are in good general agreement with those from the observed structure (grey). The cooperative nature of the folding prediction process permits favorable situations, in which contacts regions not touched by a predicted constraint (red) are still predicted correctly (black circle for RAS, dark blue on grey, no red) and false positive constraints are not strong enough to lead to incorrect contacts (left black circle Elav4, red star, no dark blue or grey). However, in unfavorable situations missing constraints may imply that contact regions are fully or partially missed (black circle, trypsin) or mostly missed (right black circle for Elav4, grey adjacent to and wider than dark blue).CC BY · PubMed Central
Figure 6 Key requirement of global statistical model for correct prediction. Evaluation of accuracy in terms of predicted contacts (A) and predicted 3D structures (B). (A) The two global models, the Bayesian network model (BNM, green [13]) and direct information model (DI, red, this work and [47]) have a consistently high rate of correctly predicted contacts (true positives) among the top NC ranked residue pairs; two local models, mutual information (MI, green, equation 1) and SCA (black, [66]) have a consistently lower rate of true positives. Here, local refers to statistical independence of each pair i,j, while global refers to statistical consistency of all pairs. In (B), only the predicted 3D structures (green, BNM; red, EIC) for the global models agree well with the observed structure (grey); Cα-RMSDs is calculated over the number or residues in parentheses (Pymol sessions for all structures in Web Appendix A4). Attempts to generate 3D structures for the two local methods MI and SCA failed (not shown). Comparing (A) and (B) confirms that a higher rate of true positives for contact prediction leads to better 3D structures and that for DI one needs at least a true positive rate of about 0.5 for about 100 predicted contacts, depending on size and other details of particular protein families. Interestingly, a false positive rate as high as about 0.3–0.5 can still be consistent with good 3D structure prediction.
Figure 6 Key requirement of global statistical model for correct prediction. Evaluation of accuracy in terms of predicted contacts (A) and predicted 3D structures (B). (A) The two global models, the Bayesian network model (BNM, green [13]) and direct information model (DI, red, this work and [47]) have a consistently high rate of correctly predicted contacts (true positives) among the top NC ranked residue pairs; two local models, mutual information (MI, green, equation 1) and SCA (black, [66]) have a consistently lower rate of true positives. Here, local refers to statistical independence of each pair i,j, while global refers to statistical consistency of all pairs. In (B), only the predicted 3D structures (green, BNM; red, EIC) for the global models agree well with the observed structure (grey); Cα-RMSDs is calculated over the number or residues in parentheses (Pymol sessions for all structures in Web Appendix A4). Attempts to generate 3D structures for the two local methods MI and SCA failed (not shown). Comparing (A) and (B) confirms that a higher rate of true positives for contact prediction leads to better 3D structures and that for DI one needs at least a true positive rate of about 0.5 for about 100 predicted contacts, depending on size and other details of particular protein families. Interestingly, a false positive rate as high as about 0.3–0.5 can still be consistent with good 3D structure prediction.CC BY · PubMed Central
Figure 7 Moderate number of distance constraints and varying number of sequences required for correct 3D structure prediction. A. How many distance constraints are needed for fold prediction? What fraction of false positives can be tolerated? With increasing number of predicted essential distance constraints (NC, horizontal axis), 3D prediction error decreases rapidly, as assessed by Cα-RMSD between the best of 20 (in each NC bin) predicted structures and the observed structure (here, for the 15 test proteins, using Pymol). Remarkably, as few as ∼NRES/2 (∼L/2) distance constraints dij (with chain distance |i−j|>5) suffice for good quality predictions below 5 Å Cα-RMSD, where NRES is the number of amino acid residues in the protein multiple sequence alignment. We therefore routinely generated candidate protein structures for up to NC = NRES distance constraints for blinded ranking (and for up to NC = 200 for other tests). Eventually the number of false positives does degrade prediction quality, e.g., for the 58 residue protein BPTI once NC is about 80 (1.5 NRES) the prediction quality is lost. In practice, we do not recommend using NC>NRES, i.e, more than about one constraint dij with |i−j|>5, per residue. B. When would it have been possible to fold from sequence? The increase in the number of sequences available in public databases (here, from successive archival releases of the PFAM collection of protein family alignments) is one of two key elements in the ability to predict protein folds from correlated mutations. Nevertheless plotting the numbers of sequences and dates shows that it would have been possible to calculate the structures up to 10 years ago for some proteins and that amazingly few sequences are sufficient. For example, although the retrospective prediction error (vertical axis, Cα-RMSD, using Pymol) for the best 3D structure (of 400 candidates each) in four protein families (Ras, SH3 domain (YES_human) and RnaseH from Ecoli) has decreased over time, the decrease is not strictly monotonic, as the result of non-systematic growth of the database. The point at which a predicted protein structure from a particular family reaches below 4 Å Cα-RMSD varies considerably. For example, while RnaseH required about 6000 sequence to dip below 4 Å error, reached around 2008, the structure of CheY could have been predicted to 3.3 Å Cα-RMSD, with only the 600 sequences available in 1999.
Figure 7 Moderate number of distance constraints and varying number of sequences required for correct 3D structure prediction. A. How many distance constraints are needed for fold prediction? What fraction of false positives can be tolerated? With increasing number of predicted essential distance constraints (NC, horizontal axis), 3D prediction error decreases rapidly, as assessed by Cα-RMSD between the best of 20 (in each NC bin) predicted structures and the observed structure (here, for the 15 test proteins, using Pymol). Remarkably, as few as ∼NRES/2 (∼L/2) distance constraints dij (with chain distance |i−j|>5) suffice for good quality predictions below 5 Å Cα-RMSD, where NRES is the number of amino acid residues in the protein multiple sequence alignment. We therefore routinely generated candidate protein structures for up to NC = NRES distance constraints for blinded ranking (and for up to NC = 200 for other tests). Eventually the number of false positives does degrade prediction quality, e.g., for the 58 residue protein BPTI once NC is about 80 (1.5 NRES) the prediction quality is lost. In practice, we do not recommend using NC>NRES, i.e, more than about one constraint dij with |i−j|>5, per residue. B. When would it have been possible to fold from sequence? The increase in the number of sequences available in public databases (here, from successive archival releases of the PFAM collection of protein family alignments) is one of two key elements in the ability to predict protein folds from correlated mutations. Nevertheless plotting the numbers of sequences and dates shows that it would have been possible to calculate the structures up to 10 years ago for some proteins and that amazingly few sequences are sufficient. For example, although the retrospective prediction error (vertical axis, Cα-RMSD, using Pymol) for the best 3D structure (of 400 candidates each) in four protein families (Ras, SH3 domain (YES_human) and RnaseH from Ecoli) has decreased over time, the decrease is not strictly monotonic, as the result of non-systematic growth of the database. The point at which a predicted protein structure from a particular family reaches below 4 Å Cα-RMSD varies considerably. For example, while RnaseH required about 6000 sequence to dip below 4 Å error, reached around 2008, the structure of CheY could have been predicted to 3.3 Å Cα-RMSD, with only the 600 sequences available in 1999.CC BY · PubMed Central
Figure 8 Computational pipeline for protein folding. The MSA for the protein family is typically generated by a sequence similarity search in a large database of protein sequences to collect related sequences that are likely to have similar 3D structures. Correlations between sequence positions i and j are calculated from observed frequencies of amino acids in single MSA columns and column pairs. By inferring a minimal statistical model of full length-sequences, which is consistent with these correlations (Text S1), direct coupling strengths eij(A,B) between any pairs of residues are deduced. They help to derive distance constraints, which in turn are used to produce folded structures using the following steps: distance geometry generation of approximate folds, molecular dynamics simulated annealing using standard force fields, and chirality filtering. Here, we use MSAs from the PFAM collection of pre-aligned sequence families [1].
Figure 8 Computational pipeline for protein folding. The MSA for the protein family is typically generated by a sequence similarity search in a large database of protein sequences to collect related sequences that are likely to have similar 3D structures. Correlations between sequence positions i and j are calculated from observed frequencies of amino acids in single MSA columns and column pairs. By inferring a minimal statistical model of full length-sequences, which is consistent with these correlations (Text S1), direct coupling strengths eij(A,B) between any pairs of residues are deduced. They help to derive distance constraints, which in turn are used to produce folded structures using the following steps: distance geometry generation of approximate folds, molecular dynamics simulated annealing using standard force fields, and chirality filtering. Here, we use MSAs from the PFAM collection of pre-aligned sequence families [1].CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 84 references

Research works printed but not linked: 3

  1. KT Simons, 1999, Ab initio protein structure prediction of CASP III targets using ROSETTA., Proteins, Suppl 3, 171, 10.1002/(SICI)1097-0134(1999)37:3+<171::AID-PROT21>3.0.CO;2-Z · DOI
  2. MMT Mezard, 2009, Constraint satisfaction problems and neural networks: A statistical physics perspective., Journal of Physiology, 103, 107
  3. TR Lezon, 2006, Using the principle of entropy maximization to infer genetic interaction networks from gene expression patterns., Proceedings of the National Academy of Sciences of the United States of America, 103, 19033, 10.1073/pnas.0609152103 · DOI

Cited by

Sorted by citations

Items 301–400 of 1,005

Related

See all

Metadata

Authors
Marks, D. S., Colwell, L. J., Sheridan, R., Hopf, T. A., Pagnani, A., Zecchina, R., & Sander, C.
Affiliations
  • Harvard University (US)
  • MRC Laboratory of Molecular Biology (GB)
  • Memorial Sloan Kettering Cancer Center (US)
  • Italian institute for Genomic Medicine (IT)
  • Politecnico di Torino (IT)
Corresponding author
Marks, Debora S.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-12-07
Volume
6
Issue
12
Pages
e28766
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0028766
PMC
PMC3233603
OpenAlex
W2061042699
Cited by
1,144
References
84
Citations by year
2026: 61 · 2025: 60 · 2024: 47 · 2023: 72 · 2022: 96 · 2021: 104 · 2020: 90 · 2019: 110 · 2018: 91 · 2017: 107 · 2016: 71 · 2015: 74 · 2014: 72 · 2013: 56 · 2012: 29
FWCI
20.79
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PORTO@Iris (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • PORTO Publications Open Repository TOrino (Politecnico di Torino) (submittedVersion, cc-by)
Funders
  • Memorial Sloan-Kettering Cancer Center
  • Studienstiftung des Deutschen Volkes
  • National Institutes of Health (NIH U54, CA143798)
  • Engineering and Physical Sciences Research Council (EP/H028064/1)
  • National Cancer Institute (U54CA143798)
  • National Institute of General Medical Sciences (R01GM106303)
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 › RNA and protein synthesis mechanisms
Keywords
protein structure prediction, coevolution, maximum entropy model, multiple sequence alignment, de novo structure prediction, protein evolution, G protein-coupled receptors, protein engineering
MeSH terms
Animals, Humans, Protein Conformation, Proteins, Rhodopsin, Trypsin, Genetic Variation, Drug Design, Reproducibility of Results, Models, Statistical, Genome, Protein Structure, Tertiary, Evolution, Molecular, Entropy, Computational Biology, Catalytic Domain, Imaging, Three-Dimensional

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review