Our prior EVB simulations of all three systems were performed using 30 individual starting structures (endpoints of 30 individual equilibration runs initiated with different random velocities), with the EVB-FEP/US simulations performed over 51 λ windows of 200 ps/length per window (i.e. 10.2 ns/trajectory, cumulative 306 ns over 30 trajectories per system). We have repeated these simulations in the present work to ensure consistent protocols, using 10 replicas per system, based on the same initial equilibration endpoints as for our REMD-EVB simulations. Our REMD-EVB simulations were performed using up to 10 starting conformations, again using 51 λ windows per trajectory. Following from this, six individual sets of REMD-EVB simulations of increasing simulation lengths were performed as described in the Methodology section. The results of these simulations are summarized in Tables and of the mean over all trajectories. The corresponding data for the calculated reaction free energies is shown in Table .