The cooperative free energy can be divided into four contributions by introducing the concept of "stabilized geometric space" where all unary, binary, and ternary species show a common conformational geometry. First, induced PPIs characterize the protein-protein contacts in the presence of the stabilizer. Second, cooperative solvation free energy accounts for the double-counted desolvation effect from the sum of the two protein-ligand desolvation events at the three-body interface. Third, gas-phase reduced cooperativity originates from the cooperative entropic effect and can be omitted when two ligand-protein binding events are independent in the stabilized geometric space. Lastly, ligand-cooperative conformational free energy accounts for the free-energy cost to bring a ligand from different complexation states to a common stabilized geometric space. We demonstrated how the approximated cooperative free energy can be estimated from short simulations (10 ns with ten replicates) and correlates with experimental data. By analyzing the thermodynamics of the induced PPIs, we conclude that unless a ligand can induce the unary perturbation to better bind its protein partner, i.e., ∆G s geo,A +∆G s geo,B > ∆G s geo,AB , inducing any de novo PPIs only worsens the intrinsic PPIs. For example, preserving the intrinsic weak PPIs with a weak K D of 10 mM by a non-perturbative ligand already leads to a cooperativity of 100. It is noteworthy that the term cooperativity in the context of protein-protein stabilization does not directly represent the cooperative phenomenon (i.e., non-pairwise-additive contributions) commonly understood in mathematics and physics due to its asymmetricity. For instance, a non-perturbative ligand can induce high cooperativity without bringing any three-body effect, whereas a non-cooperative ligand is actually cooperative because it strongly modulates how two proteins interact with each other.