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PreprintCC BYChemRxiv

Water-Model Dependence of Absolute Binding Free Energies across the Bromodomain Family

  • Ege Altun1,2
  • İpek Sarıbal1,2
  • Asude Sezer1,2
  • Suleyman Selim Cinaroglu
  1. 1Faculty of Engineering
  2. 2Ege University
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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.

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Cite

BibTeXRIS
BibTeX
@misc{altun2026watermodel,
  title = {{Water-Model Dependence of Absolute Binding Free Energies across the Bromodomain Family}},
  author = {Ege Altun and İpek Sarıbal and Asude Sezer and Suleyman Selim Cinaroglu},
  howpublished = {ChemRxiv},
  year = {2026},
  month = oct,
  doi = {10.26434/chemrxiv.15010882/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010882/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Water-Model Dependence of Absolute Binding Free Energies across the Bromodomain Family
AU  - Ege Altun
AU  - İpek Sarıbal
AU  - Asude Sezer
AU  - Suleyman Selim Cinaroglu
PY  - 2026
DA  - 2026/10/22
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15010882/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010882/v1
AB  - 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.
ER  -