Atomistic modeling of the host-guest system As a representative example of a supramolecular host, here we focus on the coordination cage 1 reported in Figure recently employed by Takezawa et al. to host the hydrolysis of encapsulated amide guests. This is an octahedral coordination cage composed of four self-assembled electron-deficient panel ligands (2,4,6-tris(4pyridyl)-1,3,5-triazine) and six metal-based corners (cis-endcapped Pd(ii) complexes). As a first step, starting from the X-ray crystal structure reported in the literature, we built an AA model for cage 1 which was then preliminary minimized and equilibrated in explicit water solvent and in standard (room) conditions of temperature and pressure via a classical MD simulation. In particular, all the AA models used herein have been parametrized based on the General Amber Force Field (GAFF) and all simulations have been run with the GROMACS-2020.2 software 35 patched with Plumed-2.7. (details available in the Computational Methods section in the Supporting Information, SI). We analyzed the equilibrium MD trajectories to study the degree of flexibility of the cage in realistic conditions. Analysis of the evolution along the MD of, e.g., the internal volume of the cage cavity, Root Mean Square Deviation (RMSD) of the atomic positions, and of two variables (d1 and d2) estimating respectively the height and equatorial width of the octahedral cage revealed that the cage structure is rather rigid in experimentally relevant conditions (see FigureS2 in the SI). This is due to the tetrahedral T d symmetry of this cage. Differently from other examples of flexible cage hosts, cage 1 thus shows a large volume (⇠1.2 nm 3 ), open, with a rather persistent hydrophobic cavity that allows encapsulating one or multiple guest molecules in its interior (the electron-acceptor ⇡ planes of the triazine-based ligands of 1 are particularly apt at interacting with electron rich guests). As the main guest, here we focus on guest 2, an N-(2,4-Dimethoxyphenyl)thiophene-2-carboxamid, an electron-rich diaryl amide (Figure ) that was experimentally shown to produce the considerable reaction acceleration following to encapsulation in cage 1 (Figure ). The central bond in amide guest 2 can undergo hydrolysis according to the reaction schematized in Figure (top). Guest 2 is mildly apolar (logP = 2.77). Experimentally-obtained crystal structures show that cage 1 can encapsulate at the same time up to two 2 molecules in its internal cavity. An AA model was developed for guest 2, paying particular attention to the accuracy in the force field parametrization of the central amide bond dihedral, which defines the trans and cis conformers of the amide, how much one is energetically favored respect to the other, and the related transition barrier (see Figure and details in the Computational Methods section in the SI).