Here, φ is 1 for a non-perturbative ligand and φ = K A-B for the cooperative phenomenon introduced by non-cooperative PROTACs (Figure ). In fact, binding a ligand between two proteins does not only modulate the stabilized geometry by unary and binary perturbations but also via solvation perturbation. However, including the solvation perturbation in a pairwise manner requires symmetry to describe the cooperative process. In Section S5 in the Supporting Information, we derive a symmetric representation of physical cooperativity and show how solvation perturbation influences the effective binding free energy between two proteins (Figure in the Supporting Information). For simplicity, we do not extend the discussion on solvation perturbation and focus only on induced PPIs.