Our multistage approach to protein-protein docking

Our procedure starts with rigid body global search based on the Fast Fourier Transform (FFT) correlation approach that evaluates the energies of billions of docked conformations on a grid. In ClusPro 1.0 we use the docking programs DOT and ZDOCK, but in ClusPro 2.0 we have changed to our new program PIPER (Kozakov et al., 2006). PIPER is also FFT-based, but the method is extended to be used with pairwise interaction potentials. With DOT and ZDOCK we retain 20,000 and 2,000 conformations, respectively. The number of structures is reduced by rigid body filters based on empirical potentials and electrostatics calculations. Due to the use of the more accurate pairwise potential in PIPER it is enough to retain 1000 structures, and we do not need the filtering step, The retained structures are clustered using the pairwise RMSD as the distance measure and a fixed or variable clustering radius (Kozakov et al., 2005). We have shown that the 30 largest clusters contain at least one near-native structure (defined as having less that 10 Å RMSD from the ligand in the x-ray structure, calculated for ligand atoms that are within 10 Å of the fixed receptor) for 93 % of the complexes in the protein docking benchmark set. The structures in these clusters are refined by a novel medium-range optimization method called SDU (Semi-Definite programming based Underestimation) which has been developed to locate the global energy minima within the regions of the conformational space defined by the separate clusters. The procedure was used in the last rounds of CAPRI with very good results.