{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T10:16:57Z","timestamp":1787912217309,"version":"build-2784847793"},"reference-count":79,"publisher":"Wiley","issue":"48","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2025YFC2311702"],"award-info":[{"award-number":["2025YFC2311702"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2025YFC2311703"],"award-info":[{"award-number":["2025YFC2311703"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["12175195"],"award-info":[{"award-number":["12175195"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32371299"],"award-info":[{"award-number":["32371299"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["L248077"],"award-info":[{"award-number":["L248077"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Designing proteins for real\u2010world applications requires the simultaneous satisfaction of multiple physicochemical properties. Structure\u2010based de novo protein design has become the prominent design paradigm, successfully creating numerous proteins. Property optimization is commonly introduced during the sequence generation stage of protein design, i.e., inverse folding. Existing methods primarily rely on fine\u2010tuning inverse folding models to design sequences with desired characteristics. However, multi\u2010property optimization through fine\u2010tuning demands datasets annotated with multiple properties\u2014resources that remain extremely limited. Consequently, structure\u2010based protein design has not yet achieved joint optimization of multiple properties. Here, we present Discriminator\u2010Guided Inverse Folding (DGIF), a framework that guides the inverse folding model by adjusting its internal history states through an auxiliary discriminator module. The discriminator integrates multiple property predictors, each trained independently on a single\u2010property dataset, thereby enabling multi\u2010property optimization in the absence of datasets annotated with multiple properties. In addition to substantial improvements in key traits like thermostability and solubility, DGIF can generate protein sequences optimized for both properties simultaneously, with the designed proteins shifting markedly toward the Pareto front that represents optimal trade\u2010offs. Experimental results validate the effectiveness of DGIF for multi\u2010property protein design.<\/jats:p>","DOI":"10.1002\/advs.75988","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T10:32:37Z","timestamp":1781001157000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discriminator\u2010Guided Inverse Folding for Multi\u2010Property Protein Design"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuchuan","family":"Zheng","sequence":"first","affiliation":[{"name":"Institute for Advanced Study in Physics Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuyi","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Physics Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoming","family":"Liu","sequence":"additional","affiliation":[{"name":"The Sixth Laboratory National Vaccine and Serum Institute (NVSI)  Beijing China"},{"name":"National Engineering Research Center for Novel Vaccines  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Su","sequence":"additional","affiliation":[{"name":"Shanghai Artificial Intelligence Laboratory  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyu","family":"Tang","sequence":"additional","affiliation":[{"name":"Laboratoire International Associ\u00e9 Centre National de la Recherche Scientifique et University of Illinois at Urbana\u2010Champaign Unit\u00e9 Mixte de Recherche n\u00b07019 Universit\u00e9 de Lorraine B.P. 70239 Vand\u0153uvre\u2010l\u00e8s\u2010Nancy cedex 54506 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zheng","sequence":"additional","affiliation":[{"name":"The Sixth Laboratory National Vaccine and Serum Institute (NVSI)  Beijing China"},{"name":"National Engineering Research Center for Novel Vaccines  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Sixth Laboratory National Vaccine and Serum Institute (NVSI)  Beijing China"},{"name":"National Engineering Research Center for Novel Vaccines  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2926-1864","authenticated-orcid":false,"given":"Jingyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Institute for Advanced Study in Physics Zhejiang University Hangzhou China"},{"name":"School of Physics Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010024\u201002127\u20100"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010024\u201002133\u20102"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19946"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007601\u2010y"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.07.038"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006415\u20108"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010025\u201008598\u20108"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn2100"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adk8946"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10816"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c10941"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6RA16992A"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010022\u201004599\u2010z"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005983"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2022.06.154"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010biochem\u2010062917\u2010012102"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2007.03.005"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2014.09.026"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.add2187"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2025.103004"},{"key":"e_1_2_9_22_1","doi-asserted-by":"crossref","unstructured":"C.Hsu R.Verkuil andJ.Liu \u201cLearning Inverse Folding From Millions of Predicted Structures \u201dProceedings of the 39th International Conference on Machine Learning PMLR162(2022):8946\u20138970.","DOI":"10.1101\/2022.04.10.487779"},{"key":"e_1_2_9_23_1","article-title":"Improving Inverse Folding for Peptide Design With Diversity\u2010Regularized Direct Preference Optimization","author":"Park R.","year":"2024","journal-title":"arXiv"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.11.26.625397"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzaf003"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.05.20.595026"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.784165"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2020.04.003"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1614437114"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.240014"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0800938105"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8CS00014J"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/jsfa.6134"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.1c01253"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006328\u20106"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa981"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4467"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki387"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4527"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1008291"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2314853121"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1998.2397"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.70.2.430"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci400306m"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzm056"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2014.08.030"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.03458\u201013"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010023\u201001857\u20104"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/12.1.47"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.69.8.4866\u20104874.2003"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbt057"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty166"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaa1102"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742\u20104658.2012.08603.x"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2022.11.009"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12859\u2010017\u20101541\u2010z"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11274\u2010022\u201003403\u20104"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11756\u2010024\u201001707\u20104"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.20004"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adt5111"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201008370\u20104"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.7b11367"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaf064"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.558247"},{"key":"e_1_2_9_65_1","unstructured":"S.Dathathri A.Madotto andJ.Lan \u201cPlug and Play Language Models: A Simple Approach to Controlled Text Generation \u201dInternational Conference on Learning Representations (2020)."},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307851100"},{"key":"e_1_2_9_67_1","unstructured":"B.Jing S.Eismann andP.Suriana \u201cLearning From Protein Structure With Geometric Vector Perceptrons \u201dInternational Conference on Learning Representations (2021)."},{"key":"e_1_2_9_68_1","article-title":"Decoupled Weight Decay Regularization","author":"Loshchilov I.","year":"2019","journal-title":"International Conference on Learning Representations"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyq191"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade2574"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007487\u2010w"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.softx.2015.06.001"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.23354"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.2408420"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.328693"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006\u20103495(02)75577\u2010X"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.464397"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096\u2010987X(199709)18:12<1463::AID\u2010JCC4>3.0.CO;2\u2010H"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.06.014"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/bip.360221211"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.75988","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.75988","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.75988","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:26:43Z","timestamp":1787909203000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.75988"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,9]]},"references-count":79,"journal-issue":{"issue":"48","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/advs.75988"],"URL":"https:\/\/doi.org\/10.1002\/advs.75988","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,9]]},"assertion":[{"value":"2025-12-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e75988"}}