It should be noted here that the angular brackets in the above equation represent ensemble averaging which we perform over replicas. We would also like to remind the readers here that different alchemical free energy estimators, such as TI, FEP and MBAR (a more generalised verison of BAR), yield comparable results when employing ensemble simulations . Consequently, there is no reason to prefer any one estimator over the other and the claims that BAR (or MBAR) is better than TI is unfounded. We use our in-house TIES software for the analysis of simulation output to obtain free energies .