Some targets might feature certain chemical moieties which are not adequately described by the respective force field. The use inadequate parameters could explain why the use of OPLS3e leads to less outliers, as the use of custom parameters describes specific chemistries better than a general force field. Finally, the experimental results might be unsuitable. The MD calculations may not mimic the exact experimental conditions (temperature, ion concentrations, co-solvents) or the assay may only have limited correlation with the binding free energy that is targeted in the RBFE calculations. But this has no impact when comparing the different force fields, as they are all compared to the same data. Accuracy of predicted ∆G Figure shows the trend in significant differences between force fields changes when comparing accuracy in terms of back-calculated absolute binding free energies ∆G (Figure ). In this analysis, in terms of RMSE to experimental measurement, OPLS3e still significantly outperforms OpenFF-2.0 and CGenFF/MATCH*, however, its difference to OpenFF-1.0 and GAFF2.1x is no longer significant. The Consensus approach outperforms the individual open source force fields, similarly as it was for the ∆∆G We also compared force field predictions in terms of their ability to correctly rank binders based on their ∆G values by using the Kendall's τ K correlation coefficient (τ K ). This measure again reveals the same two variants outperforming the others -OPLS3e and the Consensus approach. While the pattern of significant differences between force fields is rather complex (Figure ), the differences are small in magnitude, showing that each of the force fields can be trusted to yield a compound ranking of similar quality. The Supplementary Information, Figures S.5-S.8 illustrate aggregated statistics based on ∆G per target and across all targets for all the force fields, including the consensus approaches. The corresponding values can be found in the Supplementary Information, Tables S.6-S.8. Additionally, correlation plots are provided for OpenFF-2.0, CGenFF/MATCH*, GAFF2.1x, OPLS3e and the Consensus approach in Supplementary Information, Figures S.9-S.12.