With that in mind, we note that it is often suggested that the the influence of dielectric boundary conditions wanes as the size of the QM-cluster model increases, especially for models with 150 atoms. In our own work using sizable enzyme models, including some with ionic side chains, we observe that enthalpy changes and barrier heights computed using ε = 2 or ε = 4 are virtually indistinguishable from results obtained using much larger dielectric constants. However, results for ε = 2 are distinguishable from those obtained using vacuum boundary conditions (ε = 1). That said, ThrRS proves to be something of a counterexample, in which the added flexibility of harmonic restraints combines with the dielectric boundaries to afford a qualitatively different energy profile. These results caution against drawing blanket conclusions on the basis of fixed-atom structure relaxations, as such models may be overly constrained.