For future high-throughput RBFE campaigns, we recommend dividing mutations into two groups: "easy" mutations, consisting of those with few changes in heavy atoms or rotatable bonds, and "difficult" mutations, consisting of those with many changes in heavy atoms and rotatable bonds. For the easy mutations, we recommend performing one-off simulations using very short protocols (Protocols C or D) as these have been shown to be just as accurate on both the CDK2 and PLpro systems while achieving significant computational savings. For more difficult mutations, longer protocols are appropriate (Protocols A or E), as these require more sampling time to account for the larger amount of phase space available to the ligand. For future highthroughput ABFE campaigns, we recommend the utilization of Protocol B as the best compromise between cost and accuracy. While Protocols C or D, or even shorter protocols, may be employed to further reduce cost, we caution that prior testing should be performed to ensure the requisite level of accuracy is maintained. The use of multiple replicates should be utilized to increase accuracy if resources allow it. In general, savings can be achieved by limiting the production simulation time of the solvated ligand and restraint addition steps, whereas resources should be concentrated on the protein-ligand complex step. This could be achieved by employing a mixed protocol utilizing Protocols A or B for the protein-ligand complex and Protocols C or D for the solvated ligand and restraint addition.