For RBFE calculations of KPC-2, and VIM-2 using the restraint approach, we followed the standard workflows given in Mey et al. and Hahn et al. to test how well standard RBFE methods and force field parameters perform for metalloenzymes. The perturbation network (see the SI Fig. ) was generated using LOMAP 38 v.3.1. For VIM-2 RBFE simulations of both zinc models, we have added additional edges (shown in teal in SI Fig. ) which allowed us to fully connect the network, as some of the ligands were not tested experimentally against VIM-2. Before the RBFE production runs, we minimized both the bound and unbound stages for 5000 steps. The water for both stages is equilibrated for 10 ps within the NVT ensemble