We clearly observe how, when a co-guest is also co-encapsulated with the amide guest in the cage, the crowding in the cavity augments, and the reactive cis conformer of the amide guest is more and more stabilized. The acceleration scores estimated from our computations are found in remarkable trends with the reaction acceleration observed experimentally. Overall, our computational results are found in optimal agreement with the experimental results by Takezawa et al.. , while it is worth noting that in our approach these emerge bottom-up, from a comprehensive study of the molecular and supramolecular dynamics of the host-guest system and of its key molecular equilibria. This provides a general character to this approach, as confinement-induced reaction acceleration (or deceleration) in such supramolecular (and intrinsically dynamic) host-guest system can only be explained by taking into account of all the dynamic processes that occur within them. The comprehensive picture of hydrolysis, and of how this may be modulated under confinement that we obtain here provides a general high-resolution framework for building structure-property relationships. This approach constitutes a useful general-purpose platform, useful to explore strategies towards the rational design of host-guest systems with a molecular-level control of chemical reactivity. Based on the results that we show herein, this approach offers a useful platform to explore, e.g., the effect of tuning the properties/features of the guest (e.g., hydrophobicity, symmetry, interactions, size, etc.) or of the cage cavity (e.g., structure, flexibility, hydrophobicity, etc.), as recently shown in other host-guest reactive systems. Its versatility and generality may be also useful to explore ways to gain control over the system reactivity by tuning the host-guest dynamics by using, e.g., guests mixing and guest-guest encapsulation competitions, 10 which could allow tuning the residence time and fractions of encapsulated guests within the cage cavity and, consequently, the reaction in the system. In general, all these considerations underline how gaining control over the dynamics of these systems is key to control reactivity More precisely, these dihedral force field parameters have been modified until a good agreement was reached between our cis-trans isomerization FES and the experimental free energy profile for NMA (see Figure ), modifying the main torsional parameters involved in ! bond rotation, while all the other non-bonded parameters were left unchanged (Table : in our procedure only the V 2 term for the general X-C-N-C torsion, and the V 1 and V 2 0 potential parameters specific of the H-N-C-O torsion have been modified). to keep a 300 K of temperature and 1 bar of pressure in the systems. The electrostatic interactions have been treated using the Particle Mash Ewald (PME). The cutoff for the real part of the summation was 1.0 nm. The cutoff for the van der Waals interactions was set to 1.0 nm. All of the bonds involving hydrogen atoms were constrained using the LINCS algorithm. The leap-frog integrator was used to integrate the equations of motions. All the analyses of Figure2 have been performed with Plumed-2.7. . For the contact analysis a distance cutoff of 0.5 nm has been chosen between the involved groups, paired with a switching function with parameter D 0 =0.35 nm. The Solvent Accessible Surface Area (SASA) was computed with the default probe radius of 0.14 nm.