To the purpose of our investigation, here we decided to model all possible combinations of conformers, mainly aiming to explore the presence of any correlation between confinement, crowding and the rotation of the amide bond. We also parametrized an AA model for coguest 3 (Figure ). Starting also in this case from a corresponding experimentally available crystal structure, we use this to built an additional AA model for the 2 • 3 ⇢ 1 complex, a ternary inclusion complex where one 2 guest and one 3 co-guest are simultaneously encapsulated in cage 1. Particularly interesting for this study, the 2 • 3 ⇢ 1 system was observed experimentally to produce the larger hydrolysis acceleration among all explored cases (Figure : ⇠ 14x acceleration compared to the free amide). We then ran classical MD simulations to equilibrate all the considered complexes in explicit water and in standard (room) conditions of temperature and pressure (at least 1 µs for each system -see SI for details). From the equilibrium MD trajectories, we then extracted multiple data indicative of the encapsulation (Figure ). When in the cage, 2 tends to stay shifted from the geometrical center of the cavity to maximize interactions with the walls, with the 2 trans conformer showing in general a larger shift compared to 2 cis (Figure ). This is imputable to the thiophene ring, which tends to partially stick out of the cavity preferring interaction with the solvent (scheme of Figure , top: in cyan). Co-encapsulation with 3 induces a larger decentralization of the amide guests. Noteworthy, the augmented growing in such a case is observed to causes a significant reduction in terms of 2 cis mobility in the cage cavity, as evidenced by the narrower distribution in Figure (solid red curve). This behavior correlates with an augmented number of contacts between 2 and the cage 1 (Figure ). In general, the 2 cis guest shows increased contacts than the 2 trans one (augmented guest-cage interaction), while this trends is even increased when co-guest 3 is also present within 1 (higher crowding). We will discuss The Solvent Accessible Surface Area (SASA) of the guests shows that 2 is less exposed to the solvent when this is encapsulated within 1, and even less when this is co-encapsulated together with 3 (Figure ). In general, we observe that the 2 cis conformer has a smaller SASA, and is mode compact than 2 trans in all cases. These SASA and contacts data provide information on the different packing of the 2 cis and 2 trans conformers within the cage in increasing crowding conditions. These are consistent with the FESs reconstructed from the histograms extracted from the MD of Figure , where it is evident how 2 cis allows for a tighter packing within the cage (bottom). At the same time, the 2 cis conformer is found less mobile within 1, as it is demonstrated by a narrower FES dark minimum (minimum energy configuration) compared to that of the 2 trans conformer (top).