{
  "abstract": "Proteins evolved for native biological contexts often fail when deployed in new cellular environments or therapeutic settings. We present ProVADA, a test-time framework that steers a pretrained protein generator toward externally defined properties while preserving functional constraints. Its Mixture-Adaptation Directed Annealing sampler combines coordinated mutations, population selection, and annealing to navigate rugged objective landscapes. Experimentally, ProVADA converted secreted human renin into an active, drug-inhibitable cytosolic protease and extensively deimmunized two murine single-chain antibody fragments to reduce HLA visibility while retaining antigen recognition. ESCAPE-seq measurements confirmed substantial depletion of HLA-I binder peptides across alleles. Deimmunized FMC63 variants retained CAR-T-cell killing and showed fewer binders than a tested humanized comparator. Together, these results demonstrate that broad sequence redesign can adapt functional proteins to non-native biological contexts.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "Xiaowei Zhang",
      "orcid": "0000-0002-7749-4382"
    },
    {
      "name": "Wenhui Sophia Lu",
      "orcid": "0009-0004-6293-0737"
    },
    {
      "name": "Ben Viggiano",
      "orcid": "0000-0003-1510-7567"
    },
    {
      "name": "Kevin Reynolds",
      "orcid": "0009-0008-1058-8924"
    },
    {
      "name": "Sophia Burick",
      "orcid": "0009-0009-1160-2414"
    },
    {
      "name": "Elena Sotillo",
      "orcid": "0000-0002-3993-1932"
    },
    {
      "name": "Haoyu Dai",
      "orcid": "0009-0008-4920-6815"
    },
    {
      "name": "Geonhu Lee",
      "orcid": "0009-0009-2842-4642"
    },
    {
      "name": "Zixuan Liu",
      "orcid": "0009-0002-7131-339X"
    },
    {
      "name": "Nuoya Yang",
      "orcid": "0000-0001-6130-0291"
    },
    {
      "name": "Luis S. Mille-Fragoso",
      "orcid": "0000-0001-7072-1522"
    },
    {
      "name": "Euan Ashley",
      "orcid": "0000-0001-9418-9577"
    },
    {
      "name": "Bingfei Yu",
      "orcid": "0000-0001-5550-6701"
    },
    {
      "name": "Crystal L. Mackall",
      "orcid": "0000-0003-0359-9023"
    },
    {
      "name": "Wing Hung Wong"
    },
    {
      "name": "Xiaojing J. Gao",
      "orcid": "0000-0002-3094-1456"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c8vgxzqxxp3qy.bib",
  "cited_by": 3,
  "doi": "10.1101/2025.07.11.664238",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13742580/",
  "id": "c8vgxzqxxp3qy",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://doi.org/10.1101/2025.07.11.664238",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Protein Structure and Dynamics"
    ]
  ],
  "openalex": "W4412959583",
  "pdf_url": null,
  "pmcid": "PMC13742580",
  "pmid": "42999175",
  "published": "2026-10-18",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/c8vgxzqxxp3qy.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T12:23:23Z",
      "native_id": "PMC13742580",
      "source": "pmc",
      "url": "https://doi.org/10.1101/2025.07.11.664238"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Structure and Dynamics",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Generative steering to adapt proteins beyond native biological contexts",
  "title_text": "Generative steering to adapt proteins beyond native biological contexts",
  "type": "preprint",
  "updated_at": "2026-11-10T12:23:23Z",
  "url": "https://research.draconitic.com/paper/c8vgxzqxxp3qy",
  "venue": "bioRxiv",
  "versions": []
}