PREDICTING MOLECULAR-INTERACTIONS AND INDUCIBLE COMPLEMENTARITY - FRAGMENT DOCKING OF FAB-PEPTIDE COMPLEXES

Antibody-antigen interactions are representative of a broad class of r eceptor-ligand interactions involving both specificity and potential i nducible complementarity. To test possible mechanisms of antigen-antib ody recognition and specificity computationally, we have used a Metrop olis Monte Carlo algorithm to dock fragments of the epitope Glu-Val-Va l-Pro-His-Lys-Lys to the X-ray structures of both the free and the com plexed Fab of the antibody B13I2 (raised against the C-helix of myohem erythrin). The fragments Pro-His and Val-Pro-His, which contain residu es experimentally identified as important for binding, docked correctl y to both structures, but all tetrapeptide and larger fragments docked correctly only to the complexed Fab, even when torsional flexibility was added to the ligand. However, only tetrapeptide and larger fragmen ts showed significantly more favorable energies when docked to the com plexed Fab coordinates than when docked to either the free Fab or a no n-specific site remote from the combining site. Comparison of the free and complexed B13I2 structures revealed that atoms within 5 Angstrom of Val-Pro-His showed little movement upon peptide binding, but atoms within 5 Angstrom of the other four epitope residues showed greater mo vements. These results computationally distinguish recognition and bin ding processes with practical implications for drug design strategies. Overall, this new fragment docking approach establishes distinct role s for the ''lock-and-key'' (recognition) and the ''handshake'' (bindin g) paradigms in antibody-antigen interaction, suggests an incremental approach to incorporating flexibility in computational docking, and id entifies critical regions within receptor binding sites for ligand rec ognition. (C) 1994 Wiley-Liss, Inc.