Development and testing of an automated approach to protein docking.

A new version of GRAMM was applied to Targets 14, 18, and 19 in CAPRI Round 5. The predictions were generated without manual intervention. Ten top-ranked matches for each target were submitted. The docking was performed by a rigid-body procedure with a smoothed potential function to accommodate conformational changes. The first stage was a global search on a fine grid with a projection of a smoothed Lennard-Jones potential. The top predictions from the first stage were subjected to the conjugate gradient minimization with the same smoothed potential. The resulting local minima were reranked according to the weighted sum of Lennard-Jones potential, pairwise residue-residue statistical preferences, cluster occupancy, and the degree of the evolutionary conservation of the predicted interface. For Targets 14 and 18, the conformation of the complex was predicted with root-mean-square deviation (RMSD) of the ligand interface atoms 0.68 A and 1.88 A correspondingly. For Target 19, the interface areas on both proteins were correctly predicted. The performance of the procedure was also analyzed on the benchmark of bound-unbound protein complexes. The results show that, on average, conformations of only 3 side-chains need to be optimized during docking of unbound structures before the backbone changes become a limiting factor. The GRAMM-X docking server is available for public use at http://www.bioinformatics.ku.edu.

The role of geometric complementarity in secondary structure packing: a systematic docking study.

A strong similarity between the major aspects of protein folding and protein recognition is one of the emerging fundamental principles in protein science. A crucial importance of steric complementarity in protein recognition is a well-established fact. The goal of this study was to assess the importance of the steric complementarity in protein folding, namely, in the packing of the secondary structure elements. Although the tight packing of protein structures, in general, is a well-known fact, a systematic study of the role of geometric complementarity in the packing of secondary structure elements has been lacking. To assess the role of the steric complementarity, we used a docking procedure to recreate the crystallographically determined packing of secondary structure elements in known protein structures by using the geometric match only. The docking results revealed a significant percentage of correctly predicted packing configurations. Different types of pairs of secondary structure elements showed different degrees of steric complementarity (from high to low: beta-beta, loop-loop, alpha-alpha, and alpha-beta). Interestingly, the relative contribution of the steric match in different types of pairs was correlated with the number of such pairs in known protein structures. This effect may indicate an evolutionary pressure to select tightly packed elements of secondary structure to maximize the packing of the entire structure. The overall conclusion is that the steric match plays an essential role in the packing of secondary structure elements. The results are important for better understanding of principles of protein structure and may facilitate development of better methods for protein structure prediction.

Docking of protein models.

An adequate description of entire genomes has to include information on the three-dimensional (3D) structure of proteins. Most of these protein structures will be determined by high-throughput modeling procedures. Thus, a structure-based analysis of the network of protein-protein interactions in genomes requires docking methodologies that are capable of dealing with significant structural inaccuracies in the modeled structures of proteins. We present a systematic study of the applicability of our low-resolution docking method to protein models of different accuracies. A representative nonredundant set of 475 cocrystallized protein-protein complexes was used to build an array of models of each protein in the set. A sophisticated procedure was created to generate the models with RMS deviations of 1, 2, 3,., 10 A from the crystal structure. The docking was performed for all the models, and the predictions were compared with the configurations of the original cocrystallized complexes. Statistical analysis showed that the low-resolution docking can determine the gross structural features of protein-protein interactions for a significant percent of complexes of highly inaccurate protein models. Such predictions may serve as starting points for a more detailed structural analysis, as well as complement experimental and computational data on protein-protein interactions obtained by other techniques.