The calculations we run for adamantane-bicyclononane and adamantane-bicyclononane with NDE are the green arrows ΔG1, ΔGb, ΔGw with green arrow ΔG2 for adamantane-bicyclononane and dashed green arrow ΔG2_3b for adamantane-bicyclononane with NDE. The meaning of each simulation is the same as in Fig. 6, with panel (a) showing the absolute "binding" free energy for each molecule and panel (b) showing the relative "binding" free energy. For adamantane-bicyclononane specifically, the bottom absolute simulation ΔG2 starts from the topology based on the structure of bicyclo[3.3.1]nonane plus topology modifications to maintain the same 1-4 and internal interactions with the end state of the left relative simulation ΔGw. For adamantane-bicyclononane with NDE, the bottom absolute simulation ΔG2_3b starts from the original topology generated from the structure of bicyclo[3.3.1]nonane.