{
  "abstract": "Peptides containing noncanonical amino acids (ncAAs) are becoming increasingly important in drug discovery, but their molecular dynamics (MD) simulation remains limited by labor-intensive residue parameterization and topology preparation. Here, we present TopFor (Topology and Residue Force-Field Parameter Preparation), an open-source, peptide-oriented workflow that automates the generation of ncAA residue templates and force-field parameter files for MD simulations with AMBER using established charge-derivation methods. TopFor supports single-residue, whole-peptide, and batch parameterization workflows. The workflow was validated using the MDM2-p53 complex by comparing native AMBER residue definitions with residues processed by TopFor using three charge-derivation methods, each evaluated in three independent 100 ns MD simulations. TopFor-generated residue definitions showed structural and conformational behavior comparable to the native AMBER representation. Applicability to more complex peptide architectures was demonstrated using the head-to-tail cyclic peptide cyclosporin A and the cyclic depsipeptide cyclohexylgriselimycin. At library scale, 1,138 of 1,214 cyclohexylgriselimycin derivatives (93.7%) successfully completed TopFor parameterization and the subsequent initial AMBER-based computational workflow across two derivatization campaigns. TopFor was further integrated into a structure-based peptide discovery workflow based on the DnaN-griselimycin complex. Six GM-derived peptides were computationally prioritized and experimentally evaluated, of which four produced SPR responses against Mycobacterium smegmatis (M. smegmatis) DnaN and three showed concentration-dependent responses. TopFor reduces the manual effort required to prepare ncAA-containing peptides for MD simulations and enables their integration into both library-scale computational screening and structure-based peptide discovery workflows. Keywords: noncanonical amino acids; peptide parameterization; molecular dynamics; AMBER; AmberTools; peptide design; high-throughput virtual screening",
  "abstract_shown": true,
  "affiliations": [
    "Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "E. F. Buelbuel"
    },
    {
      "name": "H. Gnanasekar"
    },
    {
      "name": "C. Benasolo"
    },
    {
      "name": "S. Rasheed"
    },
    {
      "name": "R. Mueller"
    },
    {
      "name": "O. V. Kalinina"
    },
    {
      "affs": [
        0
      ],
      "name": "K. A. J. Bozhueyuek"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1ft6ceb8p6f23.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.05.756260",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.05.756260v1.full",
  "id": "1ft6ceb8p6f23",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.05.756260v1",
  "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|Protein Structure and Dynamics"
    ]
  ],
  "openalex": "W7221433017",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.05.756260v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-05",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1ft6ceb8p6f23.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:27:12Z",
      "native_id": "10.64898/2026.10.05.756260",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.05.756260v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "TopFor: Automated Preparation of AMBER-Compatible Parameters for Noncanonical Amino Acids in Peptides",
  "title_text": "TopFor: Automated Preparation of AMBER-Compatible Parameters for Noncanonical Amino Acids in Peptides",
  "type": "preprint",
  "updated_at": "2026-10-30T12:27:12Z",
  "url": "https://research.draconitic.com/paper/1ft6ceb8p6f23",
  "venue": "bioRxiv",
  "versions": []
}