{
  "abstract": "Motivation: RNA inverse folding, the design of RNA sequences that fold into specified target secondary structures, is a central problem in RNA design, with applications in functional RNA engineering, synthetic biology, and nucleic-acid therapeutics. This task becomes especially challenging for pseudoknotted target structures because pseudoknots break the nested structure assumed by standard thermodynamic folding models. Existing pseudoknot inverse-folding methods often rely on structure-predictor-based objectives. These methods do not directly optimize the probability that a sequence folds into the specified pseudoknotted target structure. Such optimization requires an evaluator that can assign a folding probability to the specified target within a pseudoknot-aware ensemble. Results: We present PKProbDesign, a sampling-based inverse-folding framework that directly optimizes a thermodynamic folding-probability objective for pseudoknotted targets. For each target, sampled sequences are scored by combining the folding probability of a pseudoknot-free scaffold with the conditional folding probability of the remaining extension component. On 254 unique density-2 PseudoBase++ targets, PKProbDesign achieved the highest pseudo-joint folding probability on 245 targets, compared with 6 for DesiRNA, 3 for MODENA, and none for antaRNA. Conclusions: PKProbDesign demonstrates that pseudoknot inverse folding can be formulated with target folding probability as its objective rather than structure-prediction agreement alone. By combining scaffold decomposition with conditional folding-probability evaluation based on CParty, the method provides a practical folding-probability-based approach to designing sequences for density-2 pseudoknotted targets. Availability: The source code of PKProbDesign is available at https://github.com/TakumiOtagaki/PKProbDesign.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Science Tokyo"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "T. Otagaki"
    },
    {
      "name": "J. Iwakiri"
    },
    {
      "name": "G. Terai"
    },
    {
      "name": "K. Asai"
    },
    {
      "affs": [
        0
      ],
      "name": "K. Sato"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0zrsqhc3ehmc5.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.07.09.736945",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.07.09.736945v2.full",
  "id": "0zrsqhc3ehmc5",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.07.09.736945v2",
  "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|RNA and protein synthesis mechanisms"
    ]
  ],
  "openalex": "W7168086310",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.07.09.736945v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-07-09",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/0zrsqhc3ehmc5.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:47Z",
      "native_id": "10.64898/2026.07.09.736945",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.07.09.736945v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "PKProbDesign: RNA inverse folding including pseudoknots by optimizing thermodynamic folding probability",
  "title_text": "PKProbDesign: RNA inverse folding including pseudoknots by optimizing thermodynamic folding probability",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:47Z",
  "url": "https://research.draconitic.com/paper/0zrsqhc3ehmc5",
  "venue": "bioRxiv",
  "versions": []
}