The larger ensemble size should only be required for a few systems where the ligands have flexible structure or charged groups in the alchemical regions (such as MCL1 and PTP1B cases discussed in sections 5.4 and 5.5). For instance, in our dataset of 503 ligand pairs, over 86% achieved a precision of ≤ 0.5 kcal/mol using ensemble size 5. Such a progressive increase in ensemble size would ensure an optimal use of computational resources alongside achieving the desired level of precision for most calculations and resulting improvement in accuracy of results. One may choose the threshold σ to be 0.5 kcal/mol and the floor value of ensemble size to be 5.