Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo
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Bibliographic record
Abstract
Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement. Here we estimate the stability of the conserved water molecules in 35 bromodomains via binding free energy calculations using all-atom grand canonical Monte Carlo simulations. Encouraging quantitative agreement to the available experimental evidence is found. We thus discuss the expected ease of water displacement in different bromodomains and the implications for ligand selectivity.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it