We also performed QM/QM2 simulations to better understand the relative instability of the (Z⋅PS)⊂C heterodimers vs. (E⋅PS)⊂C (see Fig. ), which lies at the heart of efficient DESC. The starting point of the simulations was (E-1⋅ps1)⊂C with a perfectly planar geometry of E-1 (Φ = 180º). We performed a relaxed scan by changing Φ in steps of 5º in both senses of rotation; the resulting energies are plotted in Fig. in orange. The blue data in Fig. correspond to the same geometries while neglecting the cage and its interactions; therefore, the energetic difference between the two curves (highlighted as gray shading) quantifies the instability of the inclusion complex. We found that rotating Φ in one direction affords a highly unstable supramolecular architecture ii (Fig. , center) that is ~0.35 eV (~8 kcal/mol) higher in energy than free Z-1⋅ps1 (Fig. ). Interestingly, rotating Φ in the opposite direction gave rise to a geometry where the cage did not markedly increase the energy (iii in Fig. and). However, in this structure, the cage assumes a bowl-like conformation, and Z-1 extrudes from the cavity, facilitating its expulsion to the solution (Supplementary Movies 3-6). The large conformational changes exhibited by the flexible cage C during the process are reminiscent of the structural dynamics of enzymes during catalysis .