AbstractHerein, we present results from MD simulations of the Michaelis complex formed between the dizinc β‐lactamase from B. fragilis and imipenem. We considered two catalytically important configurations, which differ in the presence or absence of a hydroxide bridge connecting the two zinc ions in the active site. The structural and dynamical effects induced by substrate binding, the specific roles of the conserved residues and the zinc‐bound water molecules, the near attack conformers of the Michaelis complex, and so forth, are discussed in detail. The relative stability of the two configurations was estimated from QM linear scaling calculations on the enzyme‐substrate complex combined with Poisson‐Boltzmann electrostatic calculations and normal mode calculations. Importantly, we find that the two configurations have similar energies, indicating that these two structures could readily be interchanged, thereby facilitating catalysis. The configuration with the hydroxide bound to the