{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T14:10:23Z","timestamp":1789740623407,"version":"4.0.1"},"reference-count":54,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100006224","name":"Argonne National Laboratory","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006224","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006235","name":"Lawrence Berkeley National Laboratory","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006235","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Artificial metalloenzymes (ArMs) exhibit exceptional selectivity, yet extending their reactivity beyond native cofactors remains a major challenge. While previous designs using\n                    <jats:italic>native<\/jats:italic>\n                    protein scaffolds to incorporate nonnative cofactors have been reported, de novo protein design enables tailored scaffolds that incorporate nonnative cofactors, unlocking transformations inaccessible to natural enzymes. Here, we report the computational design of de novo proteins that bind Mn(salen)\u2010based complexes for asymmetric sulfoxidation. The resulting ArMs outperform the free cofactor, achieving up to 45% yield and an enantiomeric ratio (e.r.) of 26:74 under optimized conditions. A 1.5 \u00c5 resolution crystal structure confirms the designed architecture and reveals key secondary\u2010sphere interactions that govern reactivity. Guided by these insights, rational mutagenesis enhanced performance up to 79% yield and an e.r. up to 16:84. This work establishes a general strategy for integrating complex nonnative cofactors into de novo scaffolds, enabling selective catalysts for reactions beyond the reach of natural enzymes.\n                  <\/jats:p>","DOI":"10.1002\/anie.5852828","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T13:59:00Z","timestamp":1789739940000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["De Novo Design and Structural Optimization of Mn(salen)\u2010Based Artificial Metalloenzymes for Asymmetric Sulfoxidation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3381-7976","authenticated-orcid":false,"given":"Jing\u2010Xiang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7157-144X","authenticated-orcid":false,"given":"Yunling","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Texas at Austin  Austin Texas USA"},{"name":"Department of Chemistry and Biochemistry St. Mary's College of Maryland  St. Mary's City Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6610-2857","authenticated-orcid":false,"given":"Indrek","family":"Kalvet","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Washington  Seattle Washington USA"},{"name":"Institute For Protein Design University of Washington  Seattle Washington USA"},{"name":"Howard Hughes Medical Institute University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3720-7451","authenticated-orcid":false,"given":"Amira","family":"Haque","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiguang","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7896-6217","authenticated-orcid":false,"given":"David","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Washington  Seattle Washington USA"},{"name":"Institute For Protein Design University of Washington  Seattle Washington USA"},{"name":"Howard Hughes Medical Institute University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1221-6709","authenticated-orcid":false,"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11117"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41929\u2010019\u20100385\u20105"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adh8615"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2020.01.012"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202006648"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43586\u2010021\u201000044\u2010z"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19946"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100558"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41570\u2010021\u201000339\u20105"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.1c01025"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41929\u2010023\u201001068\u20102"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.12.028"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557\u2010023\u201001435\u20103"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3CS00972F"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c13909"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.1454"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi201881p"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201707637"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010017\u201000541\u20104"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b08261"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201712757"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.8b00674"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1915054117"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201903808"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41929\u2010025\u201001350\u20105"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c18532"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.2846"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.0c10136"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adt7268"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41929\u2010025\u201001436\u20100"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.05.010"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr0306945"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja046908x"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja045995q"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jorganchem.2006.08.043"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1039\/b718915j"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jorganchem.2008.11.023"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.200802449"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/cs200258e"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.71159"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202400774"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c02742"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature16191"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26030"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003819\u20102"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcat.2007.03.016"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007487\u2010w"},{"key":"e_1_2_8_49_1","doi-asserted-by":"crossref","unstructured":"C.Discovery J.Boitreaud J.Dent et\u00a0al. \u201cChai\u20101: Decoding the Molecular Interactions of Life \u201dpreprint bioRxiv October 15 2024 https:\/\/doi.org\/10.1101\/2024.10.10.615955.","DOI":"10.1101\/2024.10.10.615955"},{"key":"e_1_2_8_50_1","doi-asserted-by":"crossref","unstructured":"S.Passaro G.Corso J.Wohlwend et\u00a0al. \u201cBoltz\u20102: Towards Accurate and Efficient Binding Affinity Prediction \u201d preprint bioRxiv June 18 2025 https:\/\/doi.org\/10.1101\/2025.06.14.659707.","DOI":"10.1101\/2025.06.14.659707"},{"key":"e_1_2_8_51_1","volume-title":"Biological Inorganic Chemistry: Structure and Reactivity","author":"Bertini I.","year":"2007"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.34.21565"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2006.10.007"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202410308"},{"key":"e_1_2_8_55_1","volume-title":"Mn(salen)\u2010Based De Novo Artificial Metalloenzyme Design","author":"Kalvet I.","year":"2026"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.5852828","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.5852828","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.5852828","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T13:59:10Z","timestamp":1789739950000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.5852828"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,18]]},"references-count":54,"alternative-id":["10.1002\/anie.5852828"],"URL":"https:\/\/doi.org\/10.1002\/anie.5852828","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,18]]},"assertion":[{"value":"2026-03-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e5852828"}}