The TYK2 and TNKS2 series' RBFE perturbations were run on the same hardware as RBFE-Space simulations. Prior to system setup, proteins were prepared using Flare V4. Ligands (GAFF2) and proteins (FF99SB) were parameterised using BioSimSpace (which uses LEaP, Antechamber and Parmchk) and solvated in TIP3P waterboxes (10Å orthorhombic shell). Each system (i.e. the ligand, protein and waters) was energy minimised (250 steps) and pre-equilibrated at λ = 0.0 using a sequence of NVT and NPT equilibration with cuda.pmemd using the BioSimSpace API. As with RBFE-Space simulations, 11 λ windows were used for each ligand perturbation, but with 4ns of sampling instead of 1ns (initial tests showed that 1ns of sampling was insufficient for systems of this complexity). For each perturbation, relative free energies of solvation and binding in kcal•mol -1 were estimated using pymbar with subsampling enabled, and discarding the first 5% of each trajectory to allow for re-equilibration at each λ value.