In mathematics and physics, the cooperative phenomenon describes the emergent properties in a many-body system that are not expected from the separate pairwise behaviors. In chemistry and biology, the term cooperativity is often used to describe the protein folding process and the allosteric modulation of enzymes upon ligand binding . Historically, cooperativity in PPI stabilization is an asymmetric quantity and usually refers to the cooperativity of the ligand, i.e., describing how the binding between a ligand and the first protein is facilitated by the presence of the second protein . although other definitions have also been used . Experimentally, cooperativity is difficult to measure because adding the second protein into a solution enriches not only the ternary complex but also the new protein-protein and protein-ligand binary complexes, and mathematical models are required to derive the absolute cooperativity (shift in the dissociation constant, K d , independent of species concentration) from the apparent cooperativity (shift in EC 50 , dependent on species concentration) . However, besides a qualitative correlation between induced PPIs and cooperativity , the exact physical interpretation of cooperativity in ternary complexes on a molecular level often remains elusive, making rational optimization of cooperativity in drug design challenging.