For KPC-2 we chose PDB ID: 6D15 for its resolution (1.30 Å) and the higher PDB validation metrics, following best practices by Hahn et al. We used Flare by Cresset to load in the PDB structure and select the more populated alternate side chain locations, based on electron density maps visualized in Flare. We used pdb4amber from AmberTools 22 to fix the atom numberings in the PDB file before protonating amino acid side chains with the H++ server. We retained all crystallographic waters and the disulfide bridge between Cys69 and Cys238 for the simulations. The crystallographic glycol molecule and additional copies of ligand 1 were removed. The crystal structure of ligand 1 bound to KPC-2 was used as the template pose from which the 15 other ligands studied in Pemberton et al. were generated using Flare. For the KPC-2 simulations, the phosphonate group was simulated as singly protonated, as suggested by Pemberton et al. VIM-2 is a B1 type metallo-β-lactamase and has two Zn 2+ ions in its active site. Zinc 1 coordinates to three histidine residues, the H3 site, whereas zinc 2 coordinates to aspartate, cysteine, and histidine, known as the DCH site. For VIM-2 (PDB ID: 6O5T), we retained chain A and prepared the protein in the same way as KPC-2, using Flare. We used the bound crystal structure of ligand 16 as a template for the other ligands, as this structure was crystalized using initial soaking conditions at a pH of 7.5. Following Pemberton et al.,