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Although coupling the genetic code expansion strategy with bioorthogonal decaging reaction has enabled conditional control over various residues, the regulation of negatively charged aspartic acid and glutamic acid side chains has primarily relied on light-triggered photodecaging, while complementary chemical-decaging methods remain limited for applications involving limited light penetration or concerns regarding potential photodamage. Here, we developed para-azidobenzyl aspartate (PABD) through the combination of computationally guided molecular design and directed evolution, establishing a small molecule-triggered, bioorthogonal approach for site-specific regulation of negative charges across diverse biological contexts. PABD-mediated decaging provides efficient and traceless restoration of native aspartate side chains under physiological conditions at molecular, cellular, and organismal levels. Using this strategy, we demonstrate chemical regulation of Cas9-mediated genome editing and ALKBH1-dependent RNA epigenetic modification in mammalian cells, and even the controlled activation of an enzyme in live animals. This work provides a generalizable bioorthogonal platform for manipulating negatively charged protein side chains, offering a versatile chemical tool for gain-of-function studies in complex biological environments.<\/jats:p>","DOI":"10.1021\/jacs.6c07245","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T19:31:17Z","timestamp":1784662277000},"page":"32124-32132","source":"Crossref","is-referenced-by-count":0,"title":["Bioorthogonal Regulation\nof Negatively Charged Protein\nSide Chains in Living Systems"],"prefix":"10.1021","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2036-8764","authenticated-orcid":true,"given":"Xianrui","family":"Zhang","sequence":"first","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]},{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7622-5576","authenticated-orcid":true,"given":"Siqi","family":"Xi","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]},{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirui","family":"Xu","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Huang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Yang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3099-8495","authenticated-orcid":true,"given":"Xinyuan","family":"Fan","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]},{"name":"Beijing Normal University , , ,","place":["Beijing, China, 100875"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0402-7417","authenticated-orcid":true,"given":"Peng R.","family":"Chen","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]},{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"issue":"7973","key":"2026080511135623500_cit1","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-023-06328-6","article-title":"Mega-scale experimental analysis of protein folding\nstability in biology and design","volume":"620","author":"Tsuboyama","year":"2023","journal-title":"Nature"},{"issue":"1","key":"2026080511135623500_cit2","doi-asserted-by":"publisher","first-page":"25138","DOI":"10.1038\/srep25138","article-title":"Folding and\nStabilization of Native-Sequence-Reversed\nProteins","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci. 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U.S.A."},{"key":"2026080511135623500_cit5","doi-asserted-by":"publisher","DOI":"10.7554\/elife.60924","article-title":"Uncovering the basis of protein-protein\ninteraction specificity with a combinatorially complete library","volume":"9","author":"Lite","year":"2020","journal-title":"eLife"},{"issue":"7959","key":"2026080511135623500_cit6","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/s41586-023-05993-x","article-title":"De novo design of protein interactions with\nlearned surface fingerprints","volume":"617","author":"Gainza","year":"2023","journal-title":"Nature"},{"issue":"1","key":"2026080511135623500_cit7","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/s41467-024-55228-4","article-title":"Exploring transition states of protein\nconformational changes via\nout-of-distribution detection in the hyperspherical latent space","volume":"16","author":"Liu","year":"2025","journal-title":"Nat. Commun."},{"issue":"1","key":"2026080511135623500_cit8","doi-asserted-by":"publisher","first-page":"7328","DOI":"10.1038\/s41467-024-51507-2","article-title":"Structure\nprediction of alternative protein conformations","volume":"15","author":"Bryant","year":"2024","journal-title":"Nat. Commun."},{"issue":"1","key":"2026080511135623500_cit9","doi-asserted-by":"publisher","first-page":"28285","DOI":"10.1038\/srep28285","article-title":"Towards a\nstructural biology of the hydrophobic effect in protein folding","volume":"6","author":"Camilloni","year":"2016","journal-title":"Sci. Rep."},{"issue":"1","key":"2026080511135623500_cit10","doi-asserted-by":"publisher","first-page":"15639","DOI":"10.1038\/ncomms15639","article-title":"Real-time\nmonitoring of hydrophobic aggregation reveals a critical role of cooperativity\nin hydrophobic effect","volume":"8","author":"Jiang","year":"2017","journal-title":"Nat. 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Rep."},{"issue":"10","key":"2026080511135623500_cit18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000982","article-title":"Conservation, variability\nand the modeling of active protein kinases","volume":"2","author":"Knight","year":"2007","journal-title":"PLoS One"},{"issue":"17","key":"2026080511135623500_cit19","doi-asserted-by":"publisher","first-page":"2200083","DOI":"10.1002\/pmic.202200083","article-title":"Impact of Asp\/Glu-ADP-ribosylation\non protein-protein interaction\nand protein function","volume":"23","author":"Pei","year":"2023","journal-title":"Proteomics"},{"issue":"26","key":"2026080511135623500_cit20","doi-asserted-by":"publisher","first-page":"5350","DOI":"10.1021\/acs.jpcb.0c02629","article-title":"Selective\nStabilization of Aspartic Acid Protonation State within a Given Protein\nConformation Occurs via Specific Molecular Association","volume":"124","author":"Bandyopadhyay","year":"2020","journal-title":"J. Phys. Chem. B"},{"issue":"1","key":"2026080511135623500_cit21","doi-asserted-by":"publisher","first-page":"2143006","DOI":"10.1080\/19420862.2022.2143006","article-title":"Deciphering\ndeamidation\nand isomerization in therapeutic proteins: Effect of neighboring residue","volume":"14","author":"Irudayanathan","year":"2022","journal-title":"mAbs"},{"issue":"5","key":"2026080511135623500_cit22","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1002\/cjoc.202400876","article-title":"Bioorthogonal\nCleavage Chemistry: Harnessing the Bond-Break\nReactions for Biomolecule Manipulations in Living Systems","volume":"43","author":"Zhu","year":"2025","journal-title":"Chin. J. Chem."},{"issue":"6","key":"2026080511135623500_cit23","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1021\/acscentsci.1c00124","article-title":"Unleashing the Power\nof Bond Cleavage Chemistry in Living Systems","volume":"7","author":"Wang","year":"2021","journal-title":"ACS Cent. Sci."},{"issue":"3","key":"2026080511135623500_cit24","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1038\/nchembio.2024","article-title":"Development and application of bond cleavage reactions\nin bioorthogonal chemistry","volume":"12","author":"Li","year":"2016","journal-title":"Nat. Chem. Biol."},{"issue":"3","key":"2026080511135623500_cit25","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1093\/nsr\/nwx010","article-title":"Bioorthogonal\nchemistry in living animals","volume":"4","author":"Fan","year":"2017","journal-title":"Natl. Sci. Rev."},{"issue":"5","key":"2026080511135623500_cit26","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1021\/acscentsci.6b00024","article-title":"Bioorthogonal\nChemical Activation of Kinases in Living\nSystems","volume":"2","author":"Zhang","year":"2016","journal-title":"ACS Cent. Sci."},{"issue":"29","key":"2026080511135623500_cit27","doi-asserted-by":"publisher","first-page":"11912","DOI":"10.1021\/ja3046958","article-title":"Photocontrol of\ntyrosine phosphorylation in mammalian cells via genetic encoding of\nphotocaged tyrosine","volume":"134","author":"Arbely","year":"2012","journal-title":"J. Am. Chem. Soc."},{"issue":"17","key":"2026080511135623500_cit28","doi-asserted-by":"publisher","first-page":"2728","DOI":"10.1002\/anie.200600264","article-title":"A genetically\nencoded photocaged tyrosine","volume":"45","author":"Deiters","year":"2006","journal-title":"Angew. Chem., Int.\nEd."},{"issue":"6","key":"2026080511135623500_cit29","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1038\/s41589-022-01251-9","article-title":"Site-specific\nencoding of photoactivity and photoreactivity into antibody fragments","volume":"19","author":"Bridge","year":"2023","journal-title":"Nat. Chem. Biol."},{"issue":"14","key":"2026080511135623500_cit30","doi-asserted-by":"publisher","first-page":"3696","DOI":"10.1016\/j.cell.2025.05.006","article-title":"Machine-learning-assisted universal protein\nactivation in living\nmice","volume":"188","author":"Wang","year":"2025","journal-title":"Cell"},{"issue":"6","key":"2026080511135623500_cit31","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1021\/ja412191m","article-title":"Genetic encoding\nof photocaged cysteine allows photoactivation\nof TEV protease in live mammalian cells","volume":"136","author":"Nguyen","year":"2014","journal-title":"J.\nAm. Chem. Soc."},{"issue":"7","key":"2026080511135623500_cit32","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202200721","article-title":"Genetic Encoding of a Photocaged\nHistidine for Light-Control of Protein Activity","volume":"24","author":"Cheung","year":"2023","journal-title":"ChemBioChem"},{"issue":"4","key":"2026080511135623500_cit33","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/s41557-024-01463-7","article-title":"Genetically encoded bioorthogonal\ntryptophan decaging in living cells","volume":"16","author":"Zhu","year":"2024","journal-title":"Nat. Chem."},{"issue":"22","key":"2026080511135623500_cit34","doi-asserted-by":"publisher","first-page":"4052","DOI":"10.1002\/anie.200900683","article-title":"A Facile System\nfor Encoding Unnatural\nAmino Acids in Mammalian Cells","volume":"48","author":"Chen","year":"2009","journal-title":"Angew. Chem.,\nInt. Ed."},{"issue":"12","key":"2026080511135623500_cit35","doi-asserted-by":"publisher","first-page":"4086","DOI":"10.1021\/ja910688s","article-title":"Genetically encoded photocontrol of protein localization\nin mammalian cells","volume":"132","author":"Gautier","year":"2010","journal-title":"J. Am. Chem. Soc."},{"issue":"6","key":"2026080511135623500_cit36","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.31635\/ccschem.023.202202471","article-title":"Genetic Encoding of\na Photocaged Glutamate for Optical Control of\nProtein Functions","volume":"5","author":"Ling","year":"2023","journal-title":"CCS Chem."},{"issue":"40","key":"2026080511135623500_cit37","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202308472","article-title":"Constructing Photoactivatable\nProtein\nwith Genetically Encoded Photocaged Glutamic Acid","volume":"62","author":"Yang","year":"2023","journal-title":"Angew. Chem., Int. Ed."},{"issue":"35","key":"2026080511135623500_cit38","doi-asserted-by":"publisher","first-page":"19218","DOI":"10.1021\/jacs.3c03701","article-title":"Optical Control of Protein Functions\nvia Genetically Encoded Photocaged Aspartic Acids","volume":"145","author":"Zhang","year":"2023","journal-title":"J. Am. Chem. Soc."},{"issue":"7","key":"2026080511135623500_cit39","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1002\/cptc.202100001","article-title":"The Issue of Tissue: Approaches and Challenges to the\nLight Control of Drug Activity","volume":"5","author":"Sharma","year":"2021","journal-title":"ChemPhotoChem"},{"issue":"2","key":"2026080511135623500_cit40","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1039\/C4SC02574A","article-title":"Bioorthogonal\nprodrug activation\ndriven by a strain-promoted 1,3-dipolar cycloaddition","volume":"6","author":"Matikonda","year":"2015","journal-title":"Chem. Sci."},{"issue":"19","key":"2026080511135623500_cit41","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202116545","article-title":"Site-Specific Protein Modification with Reducing Carbohydrates","volume":"61","author":"Wu","year":"2022","journal-title":"Angew. Chem., Int. Ed."},{"issue":"12","key":"2026080511135623500_cit42","doi-asserted-by":"publisher","first-page":"7055","DOI":"10.1039\/C6SC02615J","article-title":"A genetically encoded multifunctional unnatural amino\nacid for versatile protein manipulations in living cells","volume":"7","author":"Ge","year":"2016","journal-title":"Chem. Sci."},{"key":"2026080511135623500_cit43","unstructured":"Landrum, G.\n          \n          RDKit: Open-source\ncheminformatics. 2010. https:\/\/www.rdkit.org."},{"issue":"7873","key":"2026080511135623500_cit44","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction\nwith AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"issue":"6","key":"2026080511135623500_cit45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0020161","article-title":"RosettaScripts: A Scripting Language Interface to the\nRosetta Macromolecular Modeling Suite","volume":"6","author":"Fleishman","year":"2011","journal-title":"PLoS\nOne"},{"issue":"8016","key":"2026080511135623500_cit46","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate\nstructure prediction of biomolecular\ninteractions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"issue":"11","key":"2026080511135623500_cit47","doi-asserted-by":"publisher","first-page":"4878","DOI":"10.1073\/pnas.0909141107","article-title":"Molecular\nbasis for the high-affinity binding\nand stabilization of firefly luciferase by PTC124","volume":"107","author":"Auld","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"6096","key":"2026080511135623500_cit48","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1126\/science.1225829","article-title":"A Programmable Dual-RNA\u2013Guided\nDNA Endonuclease\nin Adaptive Bacterial Immunity","volume":"337","author":"Jinek","year":"2012","journal-title":"Science"},{"issue":"1","key":"2026080511135623500_cit49","doi-asserted-by":"publisher","first-page":"7208","DOI":"10.1038\/s41467-025-62606-z","article-title":"The hidden\nrisks of\nCRISPR\/Cas: structural variations and genome integrity","volume":"16","author":"Aussel","year":"2025","journal-title":"Nat. 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