To carry out model interpretation in this study, we used SHAP feature importances. SHAP (SHapley Additive exPlanations) is an importance-based algorithm with the advantage of explaining the models both globally and locally was used to compute the AUC-ROC. PM6_COSMO MM Eint: Each P-L complex underwent simple MM energy minimization (amber19sb, igb7), from which the interaction energy (Eint) was used to compute the AUC-ROC. B) Performance comparison between two PM6/COSMO protocols in the 5 cross-validation sets and the effect of ligand conformational sampling on the ∆H of binding. SQM/MM ∆H: Each P-L complex underwent SQM/MM energy minimization, where the SQM part (PM6/COSMO) included the ligand and the MM part (amber19sb, igb7) the protein and ions. In addition, each compound underwent thorough conformational sampling with Macromodel (OPLS2005, max 3000 conformers per molecule), and was subsequently optimized using PM6/COSMO. The conformer with the lowest molecular free energy was used to compute the ligand's deformation energy and subsequently the ∆H of binding, which was used eventually to compute the AUC-ROC. MM ∆H: same as SQM/MM ∆H but with simple MM energy minimization (amber19sb, igb7) of the whole system before scoring. ∆H*: same as SQM/MM ∆H, but without conformational sampling with Macromodel. The ligand deformation energy was computed directly from the PM6/COSMO optimized docking poses. C) The effect of ligand deformation energy and conformational entropy on PM6/ COSMO scoring.