The ABFE thermodynamic cycle is designed with the goal to keep the adjacent stages close in phase space. We applied the restraints serially to simplify the diagnosis of issues during the development of the thermodynamic cycle. We have found that stages 1 and 4 are close enough in phase space in our final workflow to apply all restraints in parallel, saving computation time. We have used this simplification when applying our methodology to RBFE calculations (see Section 2.4 for details). We found that it is not possible to use a similar simplification to release the binding site restraints (edges F), see Section 2.3.3.