Allosteric stiffening of a portion of a protein surface is a strategy used in nature to regulate protein oligomerization and provide crucial functions for cells. However, a similar strategy to selectively control part of a compound dynamics remains elusive. Here we showed that macrocyclic hosts can remotely rigidify part of a molecule, implying that this part need not be included inside a macrocycle to be stiffened. In particular, multiple binding by synthetic hosts CB[7] and CB[8] can selectively rigidify fragments of a tetratopic molecule in water causing a gradual stiffening from the periphery to the core. This suggests that protein dynamics (and so function) could be tuned by targeted multiple external binding.