Despite the good correlation between the approximated cooperative free energy and experiment for the eight examples, we would like to stress that the assumption of fixed protein-ligand conformation may sometimes be violated. While many protein-ligand complexes have similar ligand binding poses in binary and ternary forms with small molecules (Figure ) and macrocycles (Figure ), other ligands such as lenalidomide, pomalidomide, and SLF-1a show a different binding mode between binary and ternary complex or involve a conformational transition of the protein to recruit the third binding partner (Figure ).