Binding free energies between a protein and ligand are the paradigmatic example of the free energies that guide CADD efforts. Generally, binding free energy methods can be divided into relative binding free energies (RBFE) and absolute binding free energies (ABFE) methods (see Figure ). ABFE calculations directly yield the desired binding affinity of one molecule to a target ∆G A bind , but they are also significantly more expensive to calculate compared to the widely used RBFEs. 10, RBFE calculations yield the difference between two candidates in different environments (∆G BAwater and ∆G BA complex ) which then can be used to recover their binding free energy difference ∆∆G BA bind . Both methods can be used to generate an FE network based on multiple ∆∆G BA bind (see Figure ). The FE network can then be translated into a ranking of all candidates, provided the candidates are connected by at least one relative comparison (see Figure ). The resulting ranking can be used, for example, as a priority list, helping to steer drug discovery efforts in the direction of improving ligand potency.