{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T10:03:14Z","timestamp":1789639394096,"version":"4.0.0"},"reference-count":33,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000070","name":"National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"publisher","award":["R01\u2010EB031008"],"award-info":[{"award-number":["R01\u2010EB031008"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000070","name":"National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"publisher","award":["R01\u2010EB031936"],"award-info":[{"award-number":["R01\u2010EB031936"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000070","name":"National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"publisher","award":["R01\u2010EB030565"],"award-info":[{"award-number":["R01\u2010EB030565"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["NMR in Biomedicine"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Gadolinium\u2010based contrast agents (GBCAs) are indispensable tools in magnetic resonance imaging (MRI), yet their clinical use is limited by non\u2010specific tissue accumulation, low molecular specificity, and safety concerns. Protein and peptide scaffolds provide a promising alternative because they can bind metal ions with high selectivity and enable precise molecular targeting. However, identifying short peptide motifs with optimal gadolinium (Gd\n                    <jats:sup>3+<\/jats:sup>\n                    ) coordination and high relaxivity remains a major challenge. Here, we used a machine\u2010learning\u2010driven peptide evolution platform, the Protein Optimization Engineering Tool (POET), to design and optimize short Gd\u2010binding motifs that enhance longitudinal relaxivity (\n                    <jats:italic>r<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    ). Two algorithmic strategies were tested: motif\u2010based and regular\u2010expression\u2010based representations. Both algorithms were trained on an initial set of 74 twelve\u2010amino\u2010acid peptides derived from natural EF\u2010hand scaffolds. Through two rounds of directed evolution and experimental screening, POET predicted peptides with up to a 24% increase in\n                    <jats:italic>r<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    ratio compared with the best natural EF\u2010hand. Further analysis revealed that peptides exhibiting higher relaxivity generally possessed a more negative net charge and lower isoelectric point than the buffer pH, indicating stronger electrostatic stabilization of Gd\n                    <jats:sup>3+<\/jats:sup>\n                    . Sequence enrichment analysis showed that acidic and small polar residues, particularly aspartic acid, glycine, and threonine, were selectively favored during evolution, while bulky hydrophobic and basic residues were depleted. These compositional trends align with improved solubility and enhanced metal coordination. Together, these results demonstrate a generalizable framework that integrates computational evolution with biophysical screening to discover new biologically derived Gd\u2010binding motifs. This approach provides a scalable route to engineer responsive, tunable, and biocompatible MRI contrast tags for precision imaging and molecular diagnostics.\n                  <\/jats:p>","DOI":"10.1002\/nbm.70381","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:41:38Z","timestamp":1789191698000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Machine Learning\u2010Based Development of Gadolinium Binding Peptides"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3695-0986","authenticated-orcid":false,"given":"Nir A.","family":"Dayan","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering &amp; Material Science Michigan State University  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makayla","family":"Long","sequence":"additional","affiliation":[{"name":"Michigan State University College of Human Medicine  Grand Rapids Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2477-3054","authenticated-orcid":false,"given":"Nicolas","family":"Scalzitti","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering &amp; Material Science Michigan State University  East Lansing Michigan USA"},{"name":"Department of Computer Science and Engineering Michigan state university  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iliya","family":"Miralavy","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering Michigan state university  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Holmes","sequence":"additional","affiliation":[{"name":"Department of Chemistry Michigan State University  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Kocherovsky","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering Michigan state university  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6382-3245","authenticated-orcid":false,"given":"Wolfgang","family":"Banzhaf","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering Michigan state university  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7272-7570","authenticated-orcid":false,"given":"Assaf A.","family":"Gilad","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering &amp; Material Science Michigan State University  East Lansing Michigan USA"},{"name":"Department of Radiology Michigan State University  East Lansing Michigan USA"},{"name":"Faculty of Life Sciences Tel Aviv University  Tel\u2010Aviv Israel"},{"name":"School of Biomedical Engineering Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.20955"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr980440x"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-015-0275-4"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.15150025"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/b905145g"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mri.2013.03.025"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30158-8"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004424-199506000-00008"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2021.06.065"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.talanta.2020.121281"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.22214"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/1759720X19883973"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.13103"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0716-0"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4SD00132J"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.8b00363"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.2174\/157017911796117250"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b09842"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20070255"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-54167-4"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/RLI.0000000000001057"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11984-2"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.7717\/peerj\u2010pchem.24"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssynbio.2c00648"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10822-024-00558-0"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.5007"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi961821c"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0536562100"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2QI00933A"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.rli.0000184756.66360.d3"},{"key":"e_1_2_11_32_1","volume-title":"Foundations of Computer Science","author":"Aho A. V.","year":"1992"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/BFb0055923"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1039\/b510982p"}],"container-title":["NMR in Biomedicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/nbm.70381","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/nbm.70381","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/nbm.70381","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T09:12:19Z","timestamp":1789636339000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/nbm.70381"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,11]]},"references-count":33,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/nbm.70381"],"URL":"https:\/\/doi.org\/10.1002\/nbm.70381","archive":["Portico"],"relation":{},"ISSN":["0952-3480","1099-1492"],"issn-type":[{"value":"0952-3480","type":"print"},{"value":"1099-1492","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,11]]},"assertion":[{"value":"2025-12-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70381"}}