Protein–protein docking with a reduced protein model accounting for side‐chain flexibility

A protein–protein docking approach has been developed based on a reduced protein representation with up to three pseudo atoms per amino acid residue. Docking is performed by energy minimization in rotational and translational degrees of freedom. The reduced protein representation allows an efficient search for docking minima on the protein surfaces within. During docking, an effective energy function between pseudo atoms has been used based on amino acid size and physico‐chemical character. Energy minimization of protein test complexes in the reduced representation results in geometries close to experiment with backbone root mean square deviations (RMSDs) of ∼1 to 3 Å for the mobile protein partner from the experimental geometry. For most test cases, the energy‐minimized experimental structure scores among the top five energy minima in systematic docking studies when using both partners in their bound conformations. To account for side‐chain conformational changes in case of using unbound protein conformations, a multicopy approach has been used to select the most favorable side‐chain conformation during the docking process. The multicopy approach significantly improves the docking performance, using unbound (apo) binding partners without a significant increase in computer time. For most docking test systems using unbound partners, and without accounting for any information about the known binding geometry, a solution within ∼2 to 3.5 Å RMSD of the full mobile partner from the experimental geometry was found among the 40 top‐scoring complexes. The approach could be extended to include protein loop flexibility, and might also be useful for docking of modeled protein structures.