{
  "abstract": "The choice of explicit water model may affect absolute binding free energy (ABFE) predictions for bromodomains, whose conserved acetyl-lysine pockets contain structured waters. We assembled a benchmark of ten distinct bromodomain–ligand complexes with experimental isothermal titration calorimetry thermodynamics and compared four TIP-family water models, TIP3P, TIP4P, TIP5P, and TIP7P, using a common alchemical protocol. TIP3P gave the lowest point-estimate mean unsigned error (MUE), 1.56 kcal mol−1, against 1.89–2.11 kcal mol−1 for the other models, at the lowest cost. TIP7P correlated best with experiment (r = 0.73), but the experimental affinities span only 2.1 kcal mol−1, about the size of the errors of the models. The 0.55 kcal mol−1 MUE difference between TIP3P and TIP7P had a nominal 95% paired bootstrap interval that excluded zero when only the benchmark composition was resampled, but not when the calculated affinities were perturbed by their sampling-sensitivity measures or the four charged ligands were left out. No other paired difference was resolved, including after finite-size corrections for the charged ligands. The leg decomposition shows that solvent and complex contributions can compensate, so water-model effects must be judged over the complete binding cycle. With one calculation per complex and model, the higher-site TIP models gave no demonstrated accuracy benefit with this force field for 1.4–2.7 times the cost.",
  "abstract_shown": true,
  "affiliations": [
    "Faculty of Engineering",
    "Ege University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Ege Altun"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "İpek Sarıbal"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Asude Sezer"
    },
    {
      "name": "Suleyman Selim Cinaroglu",
      "orcid": "0000-0001-7120-3540"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8njkxy395a3hv.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010882/v1",
  "fulltext_url": null,
  "id": "8njkxy395a3hv",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010882/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7223180932",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15010882/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-22",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/8njkxy395a3hv.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:26Z",
      "native_id": "10.26434/chemrxiv.15010882",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010882/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "source:chemrxiv",
      "subfield": "general"
    }
  ],
  "title": "Water-Model Dependence of Absolute Binding Free Energies across the Bromodomain Family",
  "title_text": "Water-Model Dependence of Absolute Binding Free Energies across the Bromodomain Family",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:26Z",
  "url": "https://research.draconitic.com/paper/8njkxy395a3hv",
  "venue": "ChemRxiv",
  "versions": []
}