{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:07:30Z","timestamp":1791605250437,"version":"4.3.4"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>CASP16 is the most recent in a series of community experiments to rigorously assess the state of the art in areas of computational structural biology. The field has advanced enormously in recent years: in early CASPs, the assessments centered around whether the methods were at all useful. Now they mostly focus on how near we are to not needing experiments. In most areas, deep learning methods dominate, particularly AlphaFold variants and associated technology. In this round, there is no significant change in overall agreement between calculated monomer protein structures and their experimental counterparts, not because of method deficiencies but because, for most proteins, agreement is likely as high as can be obtained given experimental uncertainty. For protein complexes, huge gains in accuracy were made in the previous CASP, but there still appears to be room for further improvement. In contrast to these encouraging results, for RNA structures, the deep learning methods are notably unsuccessful at present and are not superior to traditional approaches. Both approaches still produce very poor results in the absence of structural homology. For macromolecular ensembles, the small CASP target set limits conclusions, but generally, in the absence of structural templates, results tend to be poor and detailed structures of alternative conformations are usually of relatively low accuracy. For organic ligand\u2013protein structures and affinities (important for aspects of drug design), deep learning methods are substantially more successful than traditional ones on the relatively easy CASP target set, though the results often fall short of experimental accuracy. In the less glamorous but essential area of methods for estimating the accuracy, previous results found reliable accuracy estimates at the amino acid level. The present CASP results show that the best methods are also largely effective in selecting models of protein complexes with high interface accuracy. Will upcoming method improvements overcome the remaining barriers to reaching experimental accuracy in all categories? We will have to wait until the next CASP to find out, but there are two promising trends. One is the combination of traditional physics\u2010inspired methods and deep learning, and the other is the expected increase in training data, especially for ligand\u2013protein complexes.<\/jats:p>","DOI":"10.1002\/prot.70076","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T11:48:14Z","timestamp":1762170494000},"page":"5-14","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Progress and Bottlenecks for Deep Learning in Computational Structure Biology:\n                    <scp>CASP<\/scp>\n                    Round\n                    <scp>XVI<\/scp>"],"prefix":"10.1002","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5066-7178","authenticated-orcid":false,"given":"Andriy","family":"Kryshtafovych","sequence":"first","affiliation":[{"name":"Genome Center University of California  California US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2715-335X","authenticated-orcid":false,"given":"Torsten","family":"Schwede","sequence":"additional","affiliation":[{"name":"Biozentrum University of Basel  Basel Switzerland"},{"name":"SIB Swiss Institute of Bioinformatics  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8185-1215","authenticated-orcid":false,"given":"Maya","family":"Topf","sequence":"additional","affiliation":[{"name":"Leibniz Institute of Virology and Centre for Structural Systems Biology  Hamburg Germany"},{"name":"Institute for Molecular Virology and Tumorvirology University Medical Center Hamburg\u2010Eppendorf  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8061-412X","authenticated-orcid":false,"given":"Krzysztof","family":"Fidelis","sequence":"additional","affiliation":[{"name":"Genome Center University of California  California US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3012-2282","authenticated-orcid":false,"given":"John","family":"Moult","sequence":"additional","affiliation":[{"name":"Institute for Bioscience and Biotechnology Research  Rockville Maryland USA"},{"name":"Department of Cell Biology and Molecular Genetics University of Maryland  Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26237"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.25007"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10381"},{"key":"e_1_2_8_5_1","doi-asserted-by":"crossref","unstructured":"R.Evans M.O'Neill A.Pritzel et\u00a0al. \u201cProtein Complex Prediction With AlphaFold\u2010Multimer \u201d bioRxiv 2021.2010.2004.463034 2022 https:\/\/doi.org\/10.1101\/2021.10.04.463034.","DOI":"10.1101\/2021.10.04.463034"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btad573"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43588-024-00714-4"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26850"},{"issue":"1","key":"e_1_2_8_11_1","article-title":"Modeling Protein\u2013Protein and Protein\u2013Ligand Interactions by the ClusPro Team in CASP16","volume":"94","author":"Ashizawa R.","year":"2026","journal-title":"Proteins"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26856"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.70031"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10052"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26533"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.70030"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.70044"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-022-01488-1"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.70068"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.25408"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26598"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.70040"},{"issue":"2","key":"e_1_2_8_23_1","first-page":"576","article-title":"RNA\u2010Puzzles Toolkit: A Computational Resource of RNA 3D Structure Benchmark Datasets, Structure Manipulation, and Evaluation Tools","volume":"48","author":"Magnus M.","year":"2020","journal-title":"Nucleic Acids Research"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26602"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.1700409"},{"issue":"1","key":"e_1_2_8_26_1","article-title":"The RNA\u2010Puzzles Assessments of RNA\u2010Only Targets in CASP16","volume":"94","author":"Westhof E.","year":"2026","journal-title":"Proteins"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.70072"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky314"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00285-007-0110-x"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10822-020-00289-y"},{"issue":"1","key":"e_1_2_8_31_1","first-page":"249","article-title":"Assessment of Pharmaceutical Protein\u2010Ligand Pose and Affinity Predictions in CASP16","volume":"94","author":"Gilson M. K.","year":"2026","journal-title":"Proteins"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00203"},{"key":"e_1_2_8_33_1","doi-asserted-by":"crossref","unstructured":"P.Skrinjar J.Eberhardt G.Tauriello T.Schwede andJ.Durairaj \u201cHave Protein\u2010Ligand Cofolding Methods Moved Beyond Memorisation? \u201d bioRxiv 2025 https:\/\/doi.org\/10.1101\/2025.02.03.636309.","DOI":"10.1101\/2025.02.03.636309"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.4c01267"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26612"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-0270-6_6"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-09654-8"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaf336"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.70037"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.181.4096.223"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00678-1"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2024.102973"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26584"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.70065"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2018.06.022"},{"key":"e_1_2_8_46_1","doi-asserted-by":"crossref","unstructured":"A. C.McBride F.Yu E. H.Cheng et\u00a0al. \u201cPredicting Pose Distribution of Protein Domains Connected by Flexible Linkers Is an Unsolved Problem \u201d bioRxiv 2025.04.27.650885 2025 https:\/\/doi.org\/10.1101\/2025.04.27.650885.","DOI":"10.1101\/2025.04.27.650885"},{"issue":"1","key":"e_1_2_8_47_1","doi-asserted-by":"crossref","DOI":"10.1002\/prot.70079","article-title":"Blind Prediction of Complex Water and Ion Ensembles Around RNA in CASP16","volume":"94","author":"Kretsch R. C.","year":"2026","journal-title":"Proteins"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-025-00868-9"},{"key":"e_1_2_8_49_1","volume-title":"Proceedings, Conference on Computer Vision and Pattern Recognition (CVPR)","author":"Xie Q.","year":"2020"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaf429"}],"container-title":["Proteins: Structure, Function, and Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prot.70076","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T07:42:41Z","timestamp":1767080561000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/prot.70076"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,3]]},"references-count":49,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/prot.70076"],"URL":"https:\/\/doi.org\/10.1002\/prot.70076","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/PROT.70076\/v1\/decision1","asserted-by":"object"}]},"ISSN":["0887-3585","1097-0134"],"issn-type":[{"value":"0887-3585","type":"print"},{"value":"1097-0134","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,3]]},"assertion":[{"value":"2025-10-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}