We have shown that current, out-of-the-box methods and force fields give reliable RBFE results for a serine-β-lactamase (KPC-2), with excellent correlation to experiment (R = 0.93). We have also tested two non-bonded metal parameterization options and show, for the first time, results of RBFE calculations on metallo-β-lactamases. These results suggest that carrying out a more restrained equilibration, as well as accounting for polarization effects in zinc-coordinating residues gives more predictive (R = 0.66, upgraded Amber force field) results than when using ff14SB together with harmonic restraints (R = 0.48). Furthermore, through our extensive QM/MM, MD, and RBFE simulations, we highlight some of the main issues with parameterizing metalloproteins. For example, accounting for the polarization effects on the ligand, and on the metal ions themselves may further improve the accuracy of these simulations. In future work, to effectively design inhibitors across classes of βlactamases understanding their mode of action in the different classes will be needed for targeted design choices. Having reliable computational methods for predicting binding free energies available will be essential for this goal. Different strategies can be explored in the furture for improving the ease of use and reliability of alchemical free energy methods for MBLs in particular and metalloproteins in general. Considering QM/MM alchemical approaches will likely alleviate the coordination site issues, but will increase computational costs. Improving MM-based polarisation and charge distribution may be an alternative route to approach this, or using machine learned potentials to replace the QM layer for the RBFE calculations.