In these infrequent WT-MetaD simulations, the bias was deposited every 5000 steps (10 ps of simulation time) using Gaussians of initial height of 0.12 kcal/mol, with bias factor ranging between 10 and 14 (depending on the system) for the expulsion out of the cage cavity, while we used 5 as the bias factor for the WT-MetaD simulations activating the guest encapsulation event. The deposed Gaussians had equal to 4.0, 0.04 nm, 2.0 along CV1, CV2 and CV3 respectively. For each system, the estimation of the kinetic constants (k) for the amide encapsulation/expulsion transitions in/out the cage cavity have been estimated from 50 WT-MetaD simulations. From these, we then could reconstruct all the associated thermodynamic quantities as described in the previous section above (see Equation S2-S5). As demonstrated by the data obtained for all cases, it is clear that in such host-guest systems the amide guest can be in general considered to be always inside the cage cavity (see Figure , Figure and Table in the main paper) -i.e., in Equation 5 in the main paper P in ⇠ 1 in all simulated cases.