To further examine what is driving the and confidence limits of the individual DDG values in Fig. , we analysed the alchemical free energy components from the de-charging (DG qoff ), van der Waals (DG vdW ) and re-charging (DG qon ) transitions (Fig. ) for both apo and drug-bound legs of the free energy calculations (Fig. ). As expected, for both the RNA polymerase and the DNA gyrase, there were no significant differences for the negative control mutations between the mean apo and drug-bound values of DG qoff , DG vdW and DG qon and the estimated error is generally low.