Our RBFE scheme affords up to 85% computational resource reduction when compared to the small RBFE mutations performed on the PLpro system, with the larger Ligand 4 mutation deviating more significantly but still within 1 kcal/mol on average. Our ABFE schemes yield fast one-off calculations with similar accuracy when compared to a base case of uniform and constant resource allocation on the T4 Lysozyme L99A/M102Q mutant in complex with Nphenylglycinonitrile, and several implementations become more accurate while maintaining computational efficiency as batch size increases. ABFE PLpro simulations displayed strong agreement between long-run 100 ns simulations and short-run simulations, with no significant deviation observed in the protein-ligand complex step, solvated ligand step, or overall computed