Some existing metal parameterization options include bonded, non-bonded, and cationic dummy atom models. In the bonded model, the metal-ligand coordination bonds are modelled as explicit, covalent bonds, which makes them unsuitable for RBFE calculations involving ligand transformations, but could open up new avenues for RBFE calculations using protein transformations. Cationic dummy atom models place dummy atoms around the metal center to describe the charge distribution of metals more accurately. While accurate, these models are not easy to set up, and as such, are not an attractive option for automated RBFE workflows. Finally, non-bonded models do not model the coordination bond between metals and ligands explicitly. Instead, some models make use of harmonic distance restraints and/or adjusted electrostatic and Lennard-Jones parameters. The different metal modeling options are reviewed extensively by Li and Merz 23 and different models have been benchmarked by Melse et al. 3 Methods