We note here that the EVB approach is an extensively validated approach for studying chemical reactivity in enzymatic systems, and a well-calibrated EVB potential typically provides activation free energies within 1-2 kcal mol -1 from experimental values across enzyme (variants). Our group has substantial experience of applying this approach to a range of phosphotransferases, including PTP1B and YopH, and the fact that we obtain lower activation free energies than would be expected from the changes in turnover number is unlikely to be a computational artefact of model parameterization. Taken together, this further emphasizes that the contribution of the E-loop to catalysis is both dynamic and electrostatic, and that factors such as WPD-loop sequence that alter E-loop dynamics also alter the electrostatic contributions of key E-loop residues, thus impacting activity.