{
  "abstract": "A useful protein binder is defined as much by what it does not bind as by what it does. Some applications call for one binder to cover a family of related targets; others require it to distinguish a single member from near-identical relatives. Yet, widely used deep-learning-based de novo design methods typically optimise one interaction at a time, leaving cross-reactivity and specificity to emerge during downstream screening. Here we present Odin-Multi, a binder design framework that optimises a shared binder sequence against several complexes simultaneously, applying attractive objectives to on-targets and repulsive objectives to off-targets. We benchmarked Odin-Multi in silico across three systems representing distinct cross-reactivity and specificity challenges: class B1 G protein-coupled receptors (GPCRs), testing cross-reactivity across multiple therapeutically relevant receptors; short-chain three-finger toxins, testing cross-reactivity across homologous toxin family members; and peptide-MHC (pMHC) complexes, testing specificity between near-identical target and off-target surfaces. For pairs of related class B1 GPCRs, 83.5 to 96.8% of jointly optimised designs exceeded an interaction-confidence threshold for both targets, compared with 6.8 to 36.3% of designs from single-target campaigns. For two short-chain three-finger neurotoxins, 9.2% of jointly optimised designs exceeded the corresponding threshold for both targets, compared with 0.8% of designs optimised against one toxin alone. Finally, in a pMHC specificity benchmark where target and off-target differed only in a single peptide residue, counter-selection increased the fraction of designs satisfying both the target-confidence criterion and a target-to-off-target interaction-confidence ratio of 2.5 from 6.0% to 14.2%. Experimental screening produced leads consistent with both design regimes in the two systems tested in vitro. We identified a cross-reactive toxin minibinder showing apparent nanomolar binding to the neurotoxin Erabutoxin A and to a candidate NK-shNTx-containing fraction from Naja kaouthia venom (higher-affinity fitted components of 11.95 and 34.43 nM, respectively), and a pMHC minibinder with greater target-to-off-target discrimination than a previously reported design. By treating cross-reactivity and specificity as explicit design objectives rather than screening outcomes, Odin-Multi widens the range of binding behaviours accessible to computational design.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark; Center for Translational Protein Design, Technical Univer"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "V. Brasas"
    },
    {
      "name": "C. R. Christensen"
    },
    {
      "name": "K. H. Björnsson"
    },
    {
      "name": "V. E. Moller"
    },
    {
      "name": "B. Scapolo"
    },
    {
      "name": "M. Benard-Valle"
    },
    {
      "name": "M. M. Nygaard"
    },
    {
      "name": "J. C. Nielsen"
    },
    {
      "name": "S. R. Hadrup"
    },
    {
      "name": "K. H. Johansen"
    },
    {
      "affs": [
        0
      ],
      "name": "T. P. Jenkins"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7j1dqsd0kq01f.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.08.749745",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.08.749745v1.full",
  "id": "7j1dqsd0kq01f",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.08.749745v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioengineering"
    ],
    [
      "openalex",
      "1312|Protein Structure and Dynamics"
    ]
  ],
  "openalex": "W7212165513",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.08.749745v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-08",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7j1dqsd0kq01f.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:42Z",
      "native_id": "10.64898/2026.09.08.749745",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.08.749745v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioengineering",
      "subfield": "systems-synthetic"
    }
  ],
  "title": "Specificity-driven protein binder design with Odin-Multi",
  "title_text": "Specificity-driven protein binder design with Odin-Multi",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:42Z",
  "url": "https://research.draconitic.com/paper/7j1dqsd0kq01f",
  "venue": "bioRxiv",
  "versions": []
}