As a case study, here we focus on the neat host-guest system recently reported by the group of Fujita, where the encapsulation of amide guests within a coordination cage was found to considerably enhance the amide hydrolysis. This is an interesting test case not only because one amide functional group (the peptide bond) is the structural foundation of proteins, but also because the hydrolysis of amides is a classic example of a spontaneous reaction hindered by very high kinetic barriers, which can be lowered by physical means. X-ray crystallography and NMR measurements were used in this system to characterize the encapsulation of a number of electron-rich diaryl amides into different octahedral coordination cages, differing in their metal corners, having electron-deficient walls. In particular, here we focus on the host-guest system of Figure , for which an acceleration in the amide hydrolysis of ⇠ 14x (compared to the same amide free in solution) has been experimentally reported when amide 2 is co-encapsulated with co-guest cage 3 inside cage 1 (Figure : red vs. blue curves). This has been imputed to the fact that reactive conformations of the amide guest (cis-twisted) are stabilized within the cage host. Such evidence found consistency with single-crystal X-ray diffraction analyses, showing that the amide can twist when encapsulated within the cage cavity. To obtain a submolecular-resolution insight into the behavior of such system in dynamic regime, here we combine all-atom (AA) MD and MetaD simulations that allow us to reconstruct the structural and dynamical features of this host-guest system. Ab initio MetaD simulations allow us to study the chemical reactivity of the amide guest in the conformations that are most favored within the cage cavity. Coupled with the AA-MetaD thermodynamic/kinetic study of the amide (and co-guest) exchange in-and-out the cage, we can formulate a general scheme revealing the key factors controlling the reaction enhancement in this system. We obtain results that are found in excellent agreement with the available experimental trends, as well as a flexible computational framework, which can be used, in principle, to study a variety of dynamically reactive host-guest systems and to draw structure-dynamics-reactivity relationships useful for rational design.