The alchemical approaches for absolute ligand binding free energies require explicit sampling of the ligand-protein complex with the ligand in its decoupled state (state B in Fig 7). For that, a definition of restraints prior to starting the simulations is needed. The partition function of the decoupled state, however, can be separated into the independent contributions from the apo protein, the restraints, and the internal degrees of freedom of the decoupled ligand . The simulation trajectories of the decoupled ligand (state B') are readily generated for every considered ligand in the ligand-solvation leg of the thermodynamic cycle. The simulation of an apo protein does not contain the ligand, thus a single trajectory of such a protein can be generated and later used in combination with any ligand of interest.