When energy-flow-inducing power strokes were introduced in Fig. and, the constraint in equation (M3) was imposed by changing rate constants k p +W and k p +F according to variations in shuttling rate constants. By doing so, kinetic asymmetry (K r ) is not altered during the simulation, but the magnitude of the current in equation ( ) can still change by virtue of alterations in the value of the positive factor Γ (for its mathematical expression, see SI section V B4). Instead, in Supplementary Fig. S.5 rate constants k p +W and k p -F were changed to vary energy flow and K r together. Experimentally, this could correspond to introducing an interaction between the macrocycle and the Fmoc group that affects (Supplementary Fig. S.5) or not (Fig. and) the transition state of the proximal fueling reaction, without affecting the transition state of the proximal waste-forming reaction. Note that, when binding affinities are modified as in Fig. and, the left-hand side of equation (M3) stays constant and the constraint is automatically satisfied.