Protein–Ligand Binding Free Energies from Exhaustive Docking
Bibliographic record
Abstract
We explore the use of exhaustive docking as an alternative to Monte Carlo and molecular dynamics sampling for the direct integration of the partition function for protein-ligand binding. We enumerate feasible poses for the ligand and calculate the Boltzmann factor contribution of each pose to the partition function. From the partition function, the free energy, enthalpy, and entropy can be derived. All our calculations are done with a continuum solvation model that includes solving the Poisson equation. In contrast to Monte Carlo and molecular dynamics simulations, exhaustive docking avoids (within the limitations of a discrete sampling) the question of "Have we run long enough?" due to its deterministic complete enumeration of states. We tested the method on the T4 lysozyme L99A mutant, which has a nonpolar cavity that can accommodate a number of small molecules. We tested two electrostatic models. Model 1 used a solute dielectric of 2.25 for the complex apoprotein and free ligand and 78.5 for the solvent. Model 2 used a solute dielectric of 2.25 for the complex and apoprotein but 1.0 for the free ligand. For our test set of eight molecules, we obtain a reasonable correlation with a Pearson r(2) = 0.66 using model 1. The trend in binding affinity ranking is generally preserved with a Kendall τ = 0.64 and Spearman ρ = 0.83. With model 2, the correlation is improved with a Pearson r(2) = 0.83, Kendall τ = 0.93, and Spearman ρ = 0.98. This suggests that the energy function and sampling method adequately captured most of the thermodynamics of binding of the nonpolar ligands to T4 lysozyme L99A.
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How this classification was reachedexpand
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".