In contrast, different protein-protein binding poses of the same protein pair are observed upon binding of PROTACs with the same warheads but different linker scaffolds (Figure ). Intriguingly, despite the high similarity between compounds dBET23 and dBET57 (Tanimoto similarity = 0.90), they induce both binary and unary perturbations of the CRBN conformation. Besides PROTACs, the binding poses between two proteins such as FKBP1A and mTOR can also deviate upon the binding of macrocyclic molecular glue rapamycin and small-molecule molecular glue compound-7. geo,AB and ∆G s2 geo,AB are the geometric free energies to perturb the intrinsic PPIs of the first and second stabilized binary complexes, respectively. (A): Examples with similar protein-protein binding poses (from left to right): 14-3-3/PMA2 with epibestatin (PDB ID: 3m50 ) and pyrrolidone1 (PDB ID: 3m51 ), PDL1 dimer with BMS-8 (5j8o ) and BMS-202 (5j89 ), DDB1/CDK12 with (R)-CR8 (6td3 ) and HQ461 (8bug ), pVHL/SMARCA2 with PROTAC 1 (6hay ) and PROTAC 2 (6hr2 ). (B): Examples with different stabilized protein-protein binding poses of the same protein pair (from left to right): pVHL/WDR5 with MS33 (7jto ) and MS67 (7jtp ), CRBN/BRD4 DB1 with dBET23 (6bn7 ) and dBET57 (ligand is not resolved in the experiment, 6bnb ), BTK KD /cIAP1 Bir3 with BCPyr (6w7o ) and BC5P (6w8i ), and FKBP1A/mTOR with rapamycin (1fap ) and compound 7 (8ppz ). Ligand similarity is calculated with Morgan bit fingerprint with a radius of 2 and Tanimoto similarity as implemented in the RDKit . Chemical structures of the compounds are shown in Figure in the Supporting Information.