Our initial TIES calculations only contained one compound pair involving S08, of which the deviation between the calculation and the experimental data is large. As the ESMACS simulation also shows it as an outlier, we have paired S08 with 3 other compounds for TIES simulations. The results only confirm that there is a systematic deviation in the binding free energy for S08 between calculations and experimental measurements. Based on the 4 TIES calculations for S08, the average difference between calculations and experimental data is 3.21 kcal/mol. In another word, the compound S08 needs to have a binding affinity 3.21 kcal/mol more negative in the experiments, or 3.21 kcal/mol less negative in the calculations, to make them agree with each other. This value is also in a good agreement with the ESMACS calculation, with which the data point for S08 can be shifted much closer to the regression line (Figure ).