A CONTINUUM MODEL FOR PROTEIN-PROTEIN INTERACTIONS - APPLICATION TO THE DOCKING PROBLEM

The prediction of protein-protein interactions in solution is a major goal of theoretical structural biology Here, we implement a continuum description of the thermodynamic processes involved. The model differs considerably from previous models in its use of ''molecular surface'' area to describe the hydrophobic component to the free energy of conf ormational change in solution. We have applied this model to a data se t of alternative docked conformations of protein-protein complexes whi ch were generated independently of this work. It was found previously that commonly used energy evaluation techniques fail to distinguish be tween near-native and certain non-native complexes in this data set. H ere, we found that an energy function that takes into account (1) tota l electrostatic free energy, (2) hydrophobic free energy and (3) loss in side-chain conformational energy was able to reliably discriminate between near-native and non-native configurations but only when molecu lar surface is used as a descriptor of the hydrophobic effect. It is s hown that the molecular surface and the more conventional surface desc riptor ''solvent accessible surface'' give very different quantitative measures of hydrophobicity. In terms of the contribution of different energy components to the free energy of complex formation it was foun d that loss in side-chain conformational entropy is a second order eff ect. Electrostatic interaction energy (which is commonly used to score docked conformations) was a poor indicator of complementarity when st arting from unbound conformations. It was found that electrostatic des olvation energy and the hydrophobic contribution (based on a molecular surface area descriptor) are much less sensitive to local fluctuation s in atomic structure than point-to-point interaction energies and thu s may be more suited for use as a scoring function when docking unboun d conformations, where atomic complementarity is much less apparent. W hilst a combined energy function was able to distinguish near-native f rom non-native conformations in the six systems studied here, it remai ns to be determined to what extent more sizeable conformational change s would influence the results.