The results in Figure compare four cases where: (i) 2 is free in solution (Figure : dotted curve, cis conformer in pink), (ii) 2 is encapsulated in cage 1 (dashed curve, cis in dark pink), (iii) the isomerizing 2 is co-encapsulated in cage 1 with another trans 2 guest (encapsulated 2 dimer: dot-dashed curve, cis in light red), and (iv) 2 is co-encapsulated in cage 1 with co-guest 3 (dot-dashed curve, cis in light red). The results show that the stability of the conformers of 2 is significantly affected by confinement. The free energy differences between the cis and trans conformers (Figure ) indicate that, while trans is always the most stable configuration of the guest, the cis conformer is more and more stabilized as the crowding in the cage cavity increases. The transition barrier also decreases while increasing the crowding. This is captured by the G and the K conf values, as well as by the relative probability profiles P conf ! of Figure . In particular the P conf ! plots the relative probability for different conformers (!) of 2 with respect to the trans conformer in all simulated complexes. We move from a cis:trans ratio of ⇠ 10 7 :1 for one 2 free in solution to ⇠ 10 5 :1 in the mono-encapsulated system (2 ⇢ 1), ⇠ 10 4 :1 when two 2 guests are co-encapsulated in the cage (2 2 ⇢ 1), to ⇠ 10 2 :1 in the 2 • 3 ⇢ 1 system. The 2 dimer encapsulation (2 2 ⇢ 1) system, where one of the two guests is kept fixed in a trans configuration in accordance with experiments, 10 falls in between the 2 ⇢ 1 and 2 • 3 ⇢ 1 cases. The strongly twisted at ! = ⇡/4 remains extremely unlikely in all systems, despite a similar thousand-fold stabilization via confinement. The most crowded case, 2 • 3 ⇢ 1, shows a ⇠ 10000⇥ increase in the probability for finding the more reactive cis conformer respect to the case where 2 is free in solution. This is remarkable, considered that experimentally this case is the one showing the strongest acceleration in the hydrolysis reaction. Table : Thermodynamic and kinetic data for 2 isomerization in all simulated complexes. Free energy differences ( G trans!cis ) related to the trans-to-cis isomerization, equilibrium constants for the conformational change (K conf ), the height of the free-energy barriers ( G ‡ trans!cis ) from the trans state, characteristic timescales (t trans!cis and t cis!trans ) are reported.