Figure : Distributions of skewness and excess kurtosis for ∆∆G distributions of 51 different ligand pairs. Data for some ligand pairs have been taken from Bieniek et al. with the positively charged arginine residue (R263). The phenomenon has been described in more detail in the supporting information of the study by Bhati et al. The intrinsic flexibility of this ligand leads to larger uncertainties in the predicted ∆∆G values for many of the MCL1 ligand pairs. Figure shows the variation of TIES uncertainty with the ensemble size increased to 40 replicas for 10 MCL1 ligand pairs. It is clear that the uncertainty consistently drops as the ensemble size is increased for all these cases. A similar behaviour has been reported in several studies. for the same set of MCL1 ligand pairs. It is interesting to note that the two cases with the largest uncertainties (l49-l67 in grey and l44-l23 in orange) also have large ∆∆∆G values.