For the application of RBFE calculations to the protein-ligand binding problem, one aspect of uncertainty quantification which has received less attention is the variation in results across MD packages. In a previous work by Rizzi et al. a wide array of alchemical methods were compared, including potential of mean force and weighted ensemble methods . This study reported that the variability in the absolute binding free energy across the methods tested is in the range of 0.3 to 1.0 kcal/mol. However, due to differences be-tween the methods tested comparisons are difficult to draw across alchemical methods or estimators. Moreover, unlike our current study, this study does not directly compare the performance of different MD packages using the same alchemical methods, which adds too many variables for systematic and direct comparisons to be made. The input systems used by Rizzi et al. were closely matched but with some differences arising from factors such as different Coulomb constants used by AMBER and CHARMM or differing implementations of particle-mesh Ewald methods or Lennard-Jones (LJ) cutoff schemes. Technical differences between MD codes is a recurring issue which complicates the comparison of calculations and plays an important role in the present study.