{
  "abstract": "Cyclic peptides can engage extended protein interfaces, but sequence changes that improve developability often disrupt the selected target-bound geometry. Existing property-guided design methods lack a principled way to preserve this geometry during local multiproperty optimization. Here we present RF-PepTune, which separates structural eligibility from property prioritization. Before any property score is queried, RF-PepTune evaluates single substitutions and all position-distinct pairs induced by admitted substitutions to build a parent-specific, pair-complete admission graph. Pareto Monte Carlo tree search then optimizes predicted permeability, solubility, non-fouling, and low-haemolysis scores exclusively within this graph, and selected sequences undergo full structural re-evaluation. In a matched three-arm comparison of 334 parents across MDM2, GABARAP, and MCL1, joint property-structure success rose from 10.2% without admission to 51.5% with single-substitution admission and 77.5% with pair-complete admission; pair-complete gating improved success by 26.0 percentage points over single-substitution gating (95% CI, 20.7-31.4). Property-positive but structure-failing endpoints fell from 88.3% to 9.3%. In a separate target-balanced set, all 90 prioritized outputs improved all four model-native scores while satisfying prespecified structural criteria. This work establishes pairwise structural gating as a general strategy for constrained multi-objective molecular optimization.",
  "abstract_shown": true,
  "affiliations": [
    "School of Pharmacy,Shihezi University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "Y. Hou"
    },
    {
      "name": "Y. Zhang"
    },
    {
      "name": "Z. Liu"
    },
    {
      "name": "X. Peng"
    },
    {
      "name": "Z. Liu"
    },
    {
      "name": "M. Yusupujiang"
    },
    {
      "name": "Y. Xu"
    },
    {
      "name": "J. Hu"
    },
    {
      "name": "Z. Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Yang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/78zas8pdtafmp.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.24.754053",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754053v1.full",
  "id": "78zas8pdtafmp",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754053v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioinformatics"
    ],
    [
      "openalex",
      "1312|Chemical Synthesis and Analysis"
    ]
  ],
  "openalex": "W7214889410",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754053v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/78zas8pdtafmp.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:19Z",
      "native_id": "10.64898/2026.09.24.754053",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754053v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "Pair-complete structural gating enables Pareto optimization of de novo cyclic peptides with preserved binding geometry and improved developability",
  "title_text": "Pair-complete structural gating enables Pareto optimization of de novo cyclic peptides with preserved binding geometry and improved developability",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:19Z",
  "url": "https://research.draconitic.com/paper/78zas8pdtafmp",
  "venue": "bioRxiv",
  "versions": []
}