{
  "abstract": "Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by a mechanically interlocked topology, in which the C-terminal tail is threaded through an N-terminal macrolactam ring formed by an isopeptide bond. This unique topology often confers high thermal stability and resistance to proteolytic degradation. However, the isopeptide linkage, threaded topology, and class-specific disulfide connectivity make lasso peptide structures difficult to reconstruct reliably using general-purpose structure prediction models. Here, we developed HighFold-Lasso, which combines custom covalent connectivity with lasso scaffold-guided adaptive low-noise initialization to enable conditional structure generation guided by lasso conformational priors. On a test set of 52 experimentally determined structures, HighFold-Lasso achieved a 100% lasso topology success rate, with a mean RMSD C-alpha of 1.942 Angstrom for the ring-loop region and 2.375 Angstrom for the full peptide. The framework supports modeling of the four classical lasso peptide classes (I-IV) and can represent noncanonical amino acids, providing computational support for structure-function studies and molecular engineering of lasso peptides.",
  "abstract_shown": true,
  "affiliations": [
    "Macao Polytechnic University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "C. Sen"
    },
    {
      "name": "C. Zhang"
    },
    {
      "name": "H. Yang"
    },
    {
      "name": "Y. Ge"
    },
    {
      "name": "H. Hou"
    },
    {
      "name": "N. Zhu"
    },
    {
      "name": "C. Li"
    },
    {
      "name": "J. Mo"
    },
    {
      "name": "Y. Wu"
    },
    {
      "name": "J. Guo"
    },
    {
      "name": "J. GUO"
    },
    {
      "affs": [
        0
      ],
      "name": "H. Duan"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5dwj3bq303yp5.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.14.759041",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.14.759041v1.full",
  "id": "5dwj3bq303yp5",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.14.759041v1",
  "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",
      "bioinformatics"
    ],
    [
      "openalex",
      "1312|Protein Structure and Dynamics"
    ]
  ],
  "openalex": "W7222394812",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.14.759041v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5dwj3bq303yp5.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:28:05Z",
      "native_id": "10.64898/2026.10.14.759041",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.14.759041v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "HighFold-Lasso: Topology-Guided Prediction of Lasso Peptide Structures Using AlphaFold3",
  "title_text": "HighFold-Lasso: Topology-Guided Prediction of Lasso Peptide Structures Using AlphaFold3",
  "type": "preprint",
  "updated_at": "2026-10-30T12:28:05Z",
  "url": "https://research.draconitic.com/paper/5dwj3bq303yp5",
  "venue": "bioRxiv",
  "versions": []
}