In the real system, amide hydrolysis can in principle take place both when 2 is en- capsulated in the cage cavity or when this is out of the cage (with the observed reaction coefficients determined by the probabilities for finding the different reactive conformersplanar or twisted -in the two environments). In general, the reaction acceleration a will thus depend on the likelihood that the hydrolysis of 2 occurs in vs. out of the cage. From our simulations we have seen that the conformational free energy landscape of the amide guest may change upon encapsulation (changing the relative free energy difference between cis and trans conformers). As a consequence, the probability for crossing the rotational barrier around the amide bond also changes. In particular, we could observe that the more reactive 2 cis conformer is more and more stabilized as the crowding increases in the cavity of cage 1 (Figure ). The simulations also show that the encapsulation of 2 cis within the cage cavity is considerably more stable than that of 2 trans , showing a higher affinity and retention time (Figure and Table ). Altogether, this indicates that it is more likely to observe 2 cis rather than 2 trans encapsulated within the cavity of the cage, which is consistent with the fact that the 2 cis conformer is present in the crystal structures obtained experimentally. Such a dynamic complexity is represented in the scheme of Figure . More in detail, the reactivity in the system depends on the propensity of the visited 2 conformers to react, their relative population in the different complexes, their probability of encapsulation (i.e., the relative population ratio between having 2 in the cage vs. in solution at the equilibrium), and the solvent molecules accessibility to the amide (i.e., the solvent is another key reactants) upon encapsulation. Noteworthy, all these parameters that can be extracted from our simulations.