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Here, we describe a general deep learning\u2013based design approach for solubilizing native membrane proteins while preserving their sequence, fold, active-site, and ligand-binding properties. Genetically encoded de novo protein WRAPs [water-soluble RFdiffused amphipathic proteins] surround the lipid-interacting hydrophobic surfaces, rendering them thermostable and water-soluble without the need for detergents. We design WRAPs for both monomeric and oligomeric beta-barrel outer membrane proteins and helical multipass transmembrane proteins. A 2.95-angstrom-resolution cryo\u2013electron microscopy structure of WRAPed mycobacterial porin demonstrates that WRAPs can be used for the structural determination of membrane proteins in solution. As a step toward syphilis vaccine development, we generated soluble versions of\n                    <jats:italic toggle=\"yes\">Treponema pallidum<\/jats:italic>\n                    antigens.\n                  <\/jats:p>","DOI":"10.1126\/science.adr3817","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T18:04:19Z","timestamp":1783015459000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Membrane protein solubilization and structure determination using de novo\u2013designed proteins"],"prefix":"10.1126","volume":"393","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3697-7767","authenticated-orcid":true,"given":"Ljubica","family":"Mihaljevi\u0107","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Institute for Protein Design, University of Washington, Seattle, WA, USA."},{"name":"Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0023-956X","authenticated-orcid":true,"given":"David E.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute for Protein Design, University of Washington, Seattle, WA, USA."},{"name":"Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7729-5244","authenticated-orcid":true,"given":"Pooja D.","family":"Bandawane","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute for Protein Design, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3201-4517","authenticated-orcid":true,"given":"Helen E.","family":"Eisenach","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute for Protein Design, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4297-7824","authenticated-orcid":true,"given":"Andrew J.","family":"Borst","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute for Protein Design, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0539-7011","authenticated-orcid":true,"given":"Alexis","family":"Courbet","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute for Protein Design, University of Washington, Seattle, WA, USA."},{"name":"Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA."},{"name":"Centre de Biologie Structurale, University of Montpellier, CNRS, INSERM. Montpellier, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9354-2276","authenticated-orcid":true,"given":"Connor","family":"Weidle","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute for Protein Design, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1929-3952","authenticated-orcid":true,"given":"Kenneth D.","family":"Carr","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute for Protein Design, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5095-2198","authenticated-orcid":true,"given":"Everton","family":"Bettin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, UConn Health, Farmington, CT, USA."},{"name":"Department of Medicine, UConn Health, Farmington, 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