Small Molecule Hydration Free Energies in Explicit Solvent: An Extensive Test of Fixed-Charge Atomistic Simulations
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Bibliographic record
Abstract
Using molecular dynamics free energy simulations with TIP3P explicit solvent, we compute the hydration free energies of 504 neutral small organic molecules and compare them to experiments. We find, first, good general agreement between the simulations and the experiments, with an RMS error of 1.24 kcal/mol over the whole set (i.e., about 2 kT) and a correlation coefficient of 0.89. Second, we use an automated procedure to identify systematic errors for some classes of compounds, and suggest some improvements to the force field. We find that alkyne hydration free energies are particularly poorly predicted due to problems with a Lennard-Jones well depth, and find that an alternate choice for this well depth largely rectifies the situation. Third, we study the non-polar component of hydration free energies - that is, the part that is not due to electrostatics. While we find that repulsive and attractive components of the non-polar part both scale roughly with surface area (or volume) of the solute, the total non-polar free energy does not scale with the solute surface area or volume, because it is a small difference between large components and is dominated by the deviations from the trend. While the methods used here are not new, this is a more extensive test than previous explicit solvent studies, and the size of the test set allows identification of systematic problems with force field parameters for particular classes of compounds. We believe that the computed free energies and components will be valuable to others in future development of force fields and solvation models.
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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