The additional BLUES simulations show that these four ethyl groups are very sensitive to the orientation of the guest in the cavity. Figure shows the distribution of dihedral angles of the four ethyl groups sampled in BLUES simulations started from different conformations shown in Figure . The position restraints on the guest and host ensure the orientation of the guest maintained the same in the context of simulations. Our results show that the ethyl groups' preferred orientations are dependent on the orientation of the guest (Figure , S17). For example, in Figure , one ethyl group (EG4) prefers the inward orientation whereas the outward orientation is dominated in the other three ethyl groups (EG1-3). This guest orientation is also the most populated one from clustering of initial BLUES simulations. In Figure , we can see two ethyl groups (EG1-2) mainly point inward whereas the other two groups (EG3-4) always point outward in simulations. When the guest is at the entrance of the pocket (not bound yet), the four ethyl groups share a similar preference of orientation because of the symmetry of the host (Figure ). Since the guest is not bound, more space is available in the pocket and all four ethyl groups can turn either inward or outward. The distribution of the four ethyl group orientations from simulations can be found in Figure .