The experimental activation free energies (∆G ‡ exp) were derived from the kinetic data presented in refs. . Structures were selected based on clustering analysis using the hierarchical agglomerative algorithm, as implemented in CPPTRAJ. Note that the annotated catalytic distances are average values over 6000 snapshots extracted for each state from our EVB trajectories (from 30 x individual 200 ps EVB mapping windows per stationary point/system). For a full list of reacting distances across all variants, see Tables and.