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RevFEP results on two public protein–ligand benchmark sets, the JACS set (Wang et al., 2015) and the Merck set (Schindler et al., 2020), using the curated structures from Ross et al. (2023). The page covers 19 targets and 439 ligands. Every RevFEP number comes from a production RevFEP run with the default settings in How the Benchmarks Were Run. Nothing was tuned per target.
RevFEP numbers are our own results: Revilico ran every target through the RevFEP pipeline. FEP+ numbers are not our runs. They are Schrödinger’s published FEP+ (release 21-4) predictions for the same ligands, downloaded from their public benchmark repository and scored here with the same metrics, so the two can be compared directly.

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FEP benchmark overview

Every target, with the better value in each row in bold. The set and overall averages are means of the per-target statistics, so each target counts once whatever its size. Click a target to open it below.

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Benchmark details

Pick a target to plot every ligand’s predicted against experimental binding free energy. Click a point or a ligand row to see the molecule and its values.
  • JNK1: the RevFEP run treats the two flipped binding poses of 17 molecules as separate ligands (38 entries for 21 molecules). FEP+ combines each pair into one value per molecule, so this target is not a like-for-like comparison and is left out of the averages.
  • c-Met (+1, redocked): the same six ligands as c-Met (+1), started from redocked poses instead of the poses supplied with the benchmark. It is shown to illustrate how much the starting pose matters, and is left out of the averages.
  • Ligands without an FEP+ prediction: CDK8 (1 ligand), SHP2 (1), SYK neutral (3) and SYK −1 (1) have ligands that are missing from the public FEP+ data. The plot shows them for RevFEP only, and the statistics use only the ligands with both predictions.
RevFEP predicted against experimental binding free energies

RevFEP results only (our runs): predicted against experimental binding free energy for every benchmark target. The diagonal is perfect agreement; the shaded band is ±1 kcal/mol.

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Charts

Mean per-target RMSE and Spearman correlation for RevFEP and FEP+ on each benchmark set

Averages of the per-target statistics for each benchmark set (the average rows of the overview table). RevFEP numbers are our runs; FEP+ numbers are Schrödinger's published results.

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How the Benchmarks Were Run

Every target was run through the standard RevFEP pipeline with its default settings. Nothing was tuned per target. Structures, ligand poses and protonation states are the ones published with the benchmark. RevFEP does not change the net charge of a ligand along an edge, so series that mix charge states (c-Met, Eg5, SYK) were run as separate same-charge subsets. The published FEP+ results include charge-changing edges and run each of these series as one network.

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How the Numbers Are Calculated

RevFEP’s relative free energies (ΔΔG) are combined into one ΔG per ligand. Because relative calculations fix ΔG only up to a constant, the predictions for each target are shifted so that their mean equals the mean experimental value. The FEP+ values are shifted the same way, over the same ligands.
  • RMSE and MAE are the root-mean-square and mean absolute errors of ΔG, in kcal/mol. Lower is better.
  • R² is the square of the Pearson correlation coefficient. Higher is better.
  • ρ is Spearman’s rank correlation, which measures how well the ligands are ranked. Higher is better.
Ligand-level FEP+ (release 21-4) predictions are taken from Schrödinger’s public benchmark repository, matched to RevFEP ligands by name. The experimental values in both data sets agree to within 0.01 kcal/mol for every matched ligand.

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Reading These Results

Each edge was simulated once, and a minimal spanning tree has no closed cycles, so these results come without a statistical uncertainty or a cycle-closure check. Repeat runs and networks with cycles would add an error bar and a consistency check.
R² and ρ computed on fewer than about 15 ligands (c-Met, Eg5 neutral, SYK −1, Thrombin) can change a lot when one ligand moves.
They were produced with a different force field (OPLS4), a different sampling protocol, and per-target corrections for protonation states, tautomers and alternative ring flips that were applied by experts. RevFEP runs every target the same way with no manual corrections.
The largest errors are on the +1 series (c-Met, Eg5) and on SHP2. The redocked c-Met run shows that the starting pose alone can move the RMSE from 1.87 to 0.70 kcal/mol for the same ligands.
BACE from the JACS set, and the other groups in Ross et al. (2023), have not been run with RevFEP.

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Sources

  • Wang, L. et al. Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field. J. Am. Chem. Soc. 137, 2695–2703 (2015). doi:10.1021/ja512751q
  • Schindler, C. E. M. et al. Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects. J. Chem. Inf. Model. 60, 5457–5474 (2020). doi:10.1021/acs.jcim.0c00900
  • Ross, G. A. et al. The maximal and current accuracy of rigorous protein-ligand binding free energy calculations. Commun. Chem. 6, 222 (2023). doi:10.1038/s42004-023-01019-9
  • FEP+ 21-4 ligand predictions: schrodinger/public_binding_free_energy_benchmark, 21_4_results/ligand_predictions/