Free energy landscapes of encounter complexes in protein-protein association

We report the computer generation of a high-density map of the thermodynami c properties of the diffusion-accessible encounter conformations of four re ceptor-ligand protein pairs, and use it to study the electrostatic and deso lvation components of the free energy of association. Encounter complex con formations are generated by sampling the translational/ rotational space of the ligand around the receptor, both at 5-Angstrom, and zero surface-to-su rface separations. We find that partial desolvation is always an important effect, and it becomes dominant for complexes in which one of the reactants is neutral or weakly charged. The interaction provides a slowly varying at tractive force over a small but significant region of the molecular surface . In complexes with no strong charge complementarity this region surrounds the binding site, and the orientation of the ligand in the encounter confor mation with the lowest desolvation free energy is similar to the one observ ed in the fully formed complex. Complexes with strong opposite charges exhi bit two types of behavior. In the first group, represented by barnase/barst ar, electrostatics exerts strong orientational steering toward the binding site, and desolvation provides some added adhesion within the local region of low electrostatic energy. In the second group, represented by the comple x of kallikrein and pancreatic trypsin inhibitor, the overall stability res ults from the rather nonspecific electrostatic attraction, whereas the affi nity toward the binding region is determined by desolvation interactions.