Evaluation of model refinement in <scp>CASP14</scp>

Simpkin, Adam J; Rodríguez, Filomeno Sánchez; Mesdaghi, Shahram; Kryshtafovych, Andriy; Rigden, Daniel J.

doi:10.1002/prot.26185

Cited by 25 publications

(34 citation statements)

References 37 publications

(66 reference statements)

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“…Some consideration of potential future changes can be found elsewhere in this issue. 30,31 In conclusion, we have shown that the reLLG is a useful addition…”

Section: Relevance Of Refinement Category In Caspmentioning

confidence: 65%

“…Although the best refinement groups were consistently able to improve the server‐generated refinement targets, most refinement methods degrade the AlphaFold2 models, as seen here for MR as well as for other CASP assessment measures. 30 This is in spite of the lack, in the AlphaFold2 algorithm, 10 of the explicit physics‐based knowledge employed by the most successful refinement groups (e.g., Heo et al 31 ). Figure 12 shows that, with one marginal exception (a slight improvement on an AlphaFold2 starting model), the AlphaFold2 model would have scored equal or higher on the reLLG score compared to the best refined model, even including the double‐barrelled targets starting from AlphaFold2 models.…”

Section: Discussionmentioning

confidence: 99%

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Assessing the utility of CASP14 models for molecular replacement

et al. 2021

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The assessment of CASP models for utility in molecular replacement is a measure of their use in a valuable real-world application. In CASP7, the metric for molecular replacement assessment involved full likelihood-based molecular replacement searches; however, this restricted the assessable targets to crystal structures with only one copy of the target in the asymmetric unit, and to those where the search found the correct pose. In CASP10, full molecular replacement searches were replaced by likelihood-based rigid-body refinement of models superimposed on the target using the LGA algorithm, with the metric being the refined log-likelihood-gain (LLG) score. This enabled multi-copy targets and very poor models to be evaluated, but a significant further issue remained: the requirement of diffraction data for assessment. We introduce here the relative-expected-LLG (reLLG), which is independent of diffraction data. This reLLG is also independent of any crystal form, and can be calculated regardless of the source of the target, be it X-ray, NMR or cryo-EM.We calibrate the reLLG against the LLG for targets in CASP14, showing that it is a robust measure of both model and group ranking. Like the LLG, the reLLG shows that accurate coordinate error estimates add substantial value to predicted models. We find that refinement by CASP groups can often convert an inadequate initial model into a successful MR search model. Consistent with findings from others, we show that the AlphaFold2 models are sufficiently good, and reliably so, to surpass other current model generation strategies for attempting molecular replacement phasing.

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“…Some consideration of potential future changes can be found elsewhere in this issue. 30,31 In conclusion, we have shown that the reLLG is a useful addition…”

Section: Relevance Of Refinement Category In Caspmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Assessing the utility of CASP14 models for molecular replacement

et al. 2021

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“…Further evidence of the presence of disordered and flexible regions in human EPO was retrieved based on the analysis of the structural propensity of this protein based on the modeling of its three-dimensional (3D) structure by AlphaFold2 [ 80 ], which is currently the most accurate computational methods to predict 3D protein structures from the protein sequence [ 84 ]. The use of this approach allowed visualization of the whole-length protein, including its signal peptide and regions of missing electron density in previously determined X-ray crystal structure of human EPO.…”

Section: Resultsmentioning

confidence: 99%

Erythropoietin Interacts with Specific S100 Proteins

et al. 2022

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Erythropoietin (EPO) is a clinically significant four-helical cytokine, exhibiting erythropoietic, cytoprotective, immunomodulatory, and cancer-promoting activities. Despite vast knowledge on its signaling pathways and physiological effects, extracellular factors regulating EPO activity remain underexplored. Here we show by surface plasmon resonance spectroscopy, that among eighteen members of Ca2+-binding proteins of the S100 protein family studied, only S100A2, S100A6 and S100P proteins specifically recognize EPO with equilibrium dissociation constants ranging from 81 nM to 0.5 µM. The interactions occur exclusively under calcium excess. Bioinformatics analysis showed that the EPO-S100 interactions could be relevant to progression of neoplastic diseases, including cancer, and other diseases. The detailed knowledge of distinct physiological effects of the EPO-S100 interactions could favor development of more efficient clinical implications of EPO. Summing up our data with previous findings, we conclude that S100 proteins are potentially able to directly affect functional activities of specific members of all families of four-helical cytokines, and cytokines of other structural superfamilies.

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“…The refinement category assessor, Daniel Rigden, has looked at this for a subset of seven targets, with GDT_TS values ranging from 72 to 93. 6 These are cases where the best models differed from experiment for small regions of the polypeptide chain, and refinement methods were unable to converge to the experimental structure. Of the 105 residues involved, he found 64 to be close to lattice contacts, suggesting the local conformations are determined by the crystal environment (also not provided to the participants).…”

Section: Crystal Lattice Contactsmentioning

confidence: 99%

Critical assessment of methods of protein structure prediction (CASP)—Round XIV

et al. 2021

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Critical assessment of structure prediction (CASP) is a community experiment to advance methods of computing three-dimensional protein structure from amino acid sequence. Core components are rigorous blind testing of methods and evaluation of the results by independent assessors. In the most recent experiment (CASP14), deeplearning methods from one research group consistently delivered computed structures rivaling the corresponding experimental ones in accuracy. In this sense, the results represent a solution to the classical protein-folding problem, at least for single proteins. The models have already been shown to be capable of providing solutions for problematic crystal structures, and there are broad implications for the rest of structural biology. Other research groups also substantially improved performance.Here, we describe these results and outline some of the many implications. Other related areas of CASP, including modeling of protein complexes, structure refinement, estimation of model accuracy, and prediction of inter-residue contacts and distances, are also described.

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Evaluation of model refinement in CASP14

Cited by 25 publications

References 37 publications

Assessing the utility of CASP14 models for molecular replacement

Assessing the utility of CASP14 models for molecular replacement

Erythropoietin Interacts with Specific S100 Proteins

Critical assessment of methods of protein structure prediction (CASP)—Round XIV

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