For the protein-ligand systems, we chose the alchemical double-decoupling method (DDM) instead of APR because it is often more challenging to define a suitable pulling pathway for a protein-ligand system. The protein-ligand ABFE calculations were performed outside of the OpenFF-Evaluator framework, using pAPRika and other Python tools, because a workflow to handle protein-ligand ABFE is not yet implemented in the framework. The alchemical calculation protocol is similar to those of Aldeghi et al. and Alibay et al. First, we annihilate the partial charges on the ligand in the bulk and perform the opposite in the binding site. The GBSA interactions are annihilated simultaneously with the partial charges, and the nonbonded potentials were alchemically modified with openmmtools version 0.21.5 (). To accomplish this, openmmtools introduces the following alchemical attenuation function to the GBSA potential