Convergence is in general expected to be worse in the "deletion" direction than the "insertion" direction, 39 unless the particular choice of restraints alters this balance. This may seem counter-intuitive since dissipation can be larger when inserting a ghost ligand with the protein in the apo conformation than when deleting the coupled ligand in the holo state (Figure ). While dissipation is important, convergence is partly determined by how frequent important realizations are and Jarzynski showed 39 that important realizations are particularly infrequent in the deletion direction, so that approaches like Widom insertion are practical, though not Widom deletion. Wu and Kofke showed that transitions in the direction that increases the entropy will not converge with a unidirectional estimator. However, as mentioned above, restraints can alter this balance.