In particular, the molecular crowding in the cavity of the cage was found to favor the mechanical twisting of the amides towards reactive (cis isomers) configurations. The rational design of similar synthetic molecular systems requires a detailed comprehension of (i) the molecular and chemical-physical factors that control their reactivity in space and time, and (ii) how to master them in order to produce new classes of catalytic systems. However, in such supramolecular host-guest systems, the reactivity is coupled with a dynamic equilibrium where the guests exchange in/out the cage hosts, which makes them difficult to rationalize. In general, the reactivity in such systems is controlled by several factors, such as the guests binding/unbinding, the solubility of the guests in the outer solution, the character-istic timescale for the reactions, possible entrapment in metastable states, and molecular concentrations in the system. In presence of coordination-cages, a major role in the reactivity is played by the non-covalent cavity-guest interactions. Despite notable efforts, , reaching a detailed understanding in terms of the molecular factors that control the reactivity in systems in which the molecular species are in continuous exchange is typically difficult at experimental level. Computer simulations are extremely useful to this end. Quantum mechanical (QM) approaches, or semi-empirical approaches such as Density Functional Tight Binding methods (DF-TB) have been employed to study chemical reactivity and reactive pathways with notable precision. Ab initio molecular dynamics (MD) and metadynamics simulations have been also widely adopted to study chemical reactions of reactants in reactive configuration, in cases where the reactions require crossing free-energy barriers. However, the study of such systems on timescales that allows accounting also for their supramolecular host-guest dynamics (i.e., dynamic exchange of guests in-and-out the host) is not trivial. For this reason, a comprehensive description of such complex dynamic systems has been until now difficult to attain. Recent computational approaches based on enhanced sampling methods, such as, e.g., metadynamics (MetaD), holds great potential in this sense. Recently employed, e.g., to study the isomerization of photochromic switches (azobenzenes) encapsulated in coordination cages, such approaches allowed to demonstrate the tight interplay between isomerization dynamics, molecular crowding, and host-guest exchange dynamics. This approach is versatile and holds a high potential for studying chemical reactions in host-guest systems in dynamic regimes in general.