A known issue with alchemical ABFE is the occurrence of a systematic error in predicted values. This phenomenon is partly attributed to the conformational differences between the holo and apo structures of the protein environment which represent the two end-points of the thermodynamic cycle used to calculate ABFE. Systematic errors are system-dependent; they may be absent in some cases, while occurring to different extents in different systems. Both their signs as well as magnitudes vary across systems as is evident from Figures and and Table . Further, they are independent of the approach used as we report their consistency across both EQ and NEQ approaches in our results. These errors heavily compromise the accuracy of ABFE predictions and hence make their direct application difficult.