1. Two protein-ligand binding events are uncorrelated in the gas phase (∆G s φ,gas ≈ 0). The approximated cooperative free energy only considers stabilized geometries and enables an efficient way of estimating cooperativity from a single trajectory (see Methods section). To evaluate the strength of induced PPIs and a cooperative solvation contribution in ternary complexes, MD simulations were performed to study 22 ternary complexes, including two PPI stabilizers (PPIS), ten molecular glues, and ten bifunctionals (Table ). In most of the investigated ternary complexes, the magnitude of the ternary solvation contribution is negligible in comparison to the induced PPIs, except for the complex formed by 14-3-3/ChREBP/compound 3 (PDB ID: 6ygj, Figure and), in which the three-body interface involves several atoms from the ligand and the proteins with high partial charges (Figure ). Next, we compared the calculated approximated cooperativity with the experimental cooperativity values for the eight ternary complexes for which such data was available (Table and Figure ). In most cases, induced PPIs alone are enough to show a correlation with apparent cooperativity (Figure ). We note that the underestimated cooperativity of complex WDR5/VCB/MD67 (PDB ID: 7jtp) can be attributed to the abundant water-mediated hydrogen bonds at the protein-protein interface (Figure in the Supporting Information), which is not captured in the solvation free-energy estimation using the implicit solvation method. Nonetheless, including ternary solvation free energy successfully corrects the calculated cooperativity value of complex 14-3-3/ChREBP/compound 3 (PDB ID: 6iyg) and increases the overall agreement of cooperativity prediction (Figure ).