Essential dynamics sampling simulations of the domain conformations of unliganded Escherichia coli adenylate kinase have been performed to determine whether the ligand-induced closed-domain conformation is accessible to the open unliganded enzyme. Adenylate kinase is a three- domain protein with a central CORE domain and twoflanking domains, the LID and the NMPbind domains. The sampling simulations were applied to the CORE and NMPbind domain pair and the CORE and LID domain pair separately. One aim is to compare the results to those of a similar study on the enzyme citrate synthase to determine whether a similar domain-locking mechanism operates in adenylate kinase. Although for adenylate kinase the simulations suggest that the closed-domain conformation of the unliganded enzyme is at a slightly higher free energy than the open for both domain pairs, the results are radically different to those found for citrate synthase. In adenylate kinase the targeted domain conformations could always be achieved, whereas this was not the case in citrate synthase due to an apparent free-energy barrier between the open and closed conformations. Adenylate kinase has been classified as a protein that undergoes closure through a hinge mechanism, whereas citrate synthase has been assigned to the shear mechanism. This was quantified here in terms of the change in the number of interdomain contacting atoms upon closure which showed a considerable increase in adenylate kinase. For citrate synthase this number remained largely the same, suggesting that the domain faces slide over each other during closure. This suggests that shear and hinge mechanisms of domain closure may relate to the existence or absence of an appreciable barrier to closure for the unliganded protein, as the latter can hinge comparatively freely, whereas the former must follow a more constrained path. In general though it appears a bias toward keeping the unliganded enzyme in the open-domain conformation may be a common feature of domain enzymes.