A computationally tractable strategy has been developed to re®ne protein-protein interfaces that models the effects of side-chain conformational change, solvation and limited rigid-body movement of the subunits. The proteins are described at the atomic level by a multiple copy representation of side-chains modelled according to a rotamer library on a ®xed peptide backbone. The surrounding solvent environment is described bỳ`s oft'' sphere Langevin dipoles for water that interact with the protein via electrostatic, van der Waals and ®eld-dependent hydrophobic terms. Energy re®nement is based on a two-step process in which (1) a probability-based conformational matrix of the protein side-chains is re®ned iteratively by a mean ®eld method. A side-chain interacts with the protein backbone and the probability-weighted average of the surrounding protein side-chains and solvent molecules. The resultant protein conformations then undergo (2) rigid-body energy minimization to relax the protein interface. Steps (1) and (2) are repeated until convergence of the interaction energy. The in¯uence of re®nement on side-chain conformation starting from unbound conformations found improvement in the RMSD of side-chains in the interface of protease-inhibitor complexes, and shows that the method leads to an improvement in interface geometry. In terms of discriminating between docked structures, the re®nement was applied to two classes of protein-protein complex: ®ve protease-protein inhibitor and four antibody-antigen complexes. A large number of putative docked complexes have already been generated for the test systems using our rigid-body docking program, FTDOCK. They include geometries that closely resemble the crystal complex, and therefore act as a test for the re®nement procedure. In the protease-inhibitors, geometries that resemble the crystal complex are ranked in the top four solutions for four out of ®ve systems when solvation is included in the energy function, against a background of between 26 and 364 complexes in the data set. The results for the antibody-antigen complexes are not as encouraging, with only two of the four systems showing discrimination. It would appear that these results re¯ect the somewhat different binding mechanism dominant in the two types of protein-protein complex. Binding in the protease-inhibitors appears to be``lock and key'' in nature. The ®xed backbone and mobile side-chain representation provide a good model for binding. Movements in the backbone geometry of antigens on binding represent an``induced-®t'' and provides more of a challenge for the model. Given the limitations of the conformational sampling, the ability of the energy function to discriminate between native and non-native states is encouraging. Development of the approach to include greater conformational sampling could lead to a more general solution to the protein docking problem.
The algorithm in REF uses side chain rotamers and rigid body minimization to relax the interfaces of docking results.
Rapid Refinement of Protein Interfaces Incorporating Solvation: Application to the Docking Problem
J. Mol. Biol
Chemistry Medicine