DockAnalyse: an application for the analysis of protein-protein interactions

Abstract

Background: Is it possible to identify what the best solution of a docking program is? The usual answer to this question is the highest score solution, but interactions between proteins are dynamic processes, and many times the interaction regions are wide enough to permit protein-protein interactions with different orientations and/or interaction energies. In some cases, as in a multimeric protein complex, several interaction regions are possible among the monomers. These dynamic processes involve interactions with surface displacements between the proteins to finally achieve the functional configuration of the protein complex. Consequently, there is not a static and single solution for the interaction between proteins, but there are several important configurations that also have to be analyzed.

Results: To extract those representative solutions from the docking output datafile, we have developed an unsupervised and automatic clustering application, named DockAnalyse. This application is based on the already existing DBscan clustering method, which searches for continuities among the clusters generated by the docking output data representation. The DBscan clustering method is very robust and, moreover, solves some of the inconsistency problems of the classical clustering methods like, for example, the treatment of outliers and the dependence of the previously defined number of clusters.

Conclusions: DockAnalyse makes the interpretation of the docking solutions through graphical and visual representations easier by guiding the user to find the representative solutions. We have applied our new approach to analyze several protein interactions and model the dynamic protein interaction behavior of a protein complex. DockAnalyse might also be used to describe interaction regions between proteins and, therefore, guide future flexible dockings. The application (implemented in the R package) is accessible.

Figure 1

Example of one of the DockAnalyse graphical ouput windows of a certain docking assay. This is one of the most important output windows of DockAnalyse, which shows the clustering graph of all of the docking solutions tested. The axes are the two extracted components of the computed Principal Components Analysis (PCA). The clusters found by the program are depicted in different colors, and the representative points of each cluster are highlighted. This, and all of the other DockAnalyse output representations, allow for an easy and visual interpretation of the docking procedure.

Figure 2

Initially low-scored docking solutions might be important and considered with the use of DockAnalyse. (a) Firstly, the best solutions of the original results of the PPD program with each RMS deviation values calculated are shown. Below, these optimal solutions are highlighted in the graphical representations provided by DockAnalyse. These configurations can be interpreted as a binding site with a high level of constraints that seem to describe an interaction pocket. Despìte not belonging to any representative cluster, their high interaction energies reveal this type of static contact. (b) A section of the raw output datafile of the PPD program as well as two of the graphical representation outputs obtained with DockAnalyse for these same data are depicted. The most representative DockAnalyse solution is highlighted in the three sections showing the ability of this new application to consider important alternative solutions.

Figure 3

Tridimensional visualization of the selected cluster. One of the graphical results obtained with DockAnalyse for the protein complex of PDB: 1BVN of the Protein-Protein Docking Benchmark. Cluster 14 is significant in terms of cluster members and average interaction energy. All of the ligand structures of the previously selected cluster (depicted in different colors and displayed in the "ribbons" format) are viewed in 3 D on the receptor (depicted in gray and displayed in the "ribbons" format).

Figure 4

Example of a protein complex modeling. The images (a) -> (b) -> (c) -> (d) represent the modeled structures of the solutions given by DockAnalyse for the docking between proteins Isu1 and Isu2. The structures are displayed in the "surface" and "ribbon" formats and colored in green for protein Isu1 and yellow in the case of Isu2. The iron binding pocket of each of the proteins, which is composed of 3 cysteine residues, is displayed in a "ball and stick" format and colored in magenta. Isu1 and Isu2 iron binding pockets and interaction tails are labeled. The edges attempt to show the trajectory that may occur when these proteins interact to finally acquire the desired configuration required for ISC biogenesis.

Figure 5

DockAnalyse: how and when. Schematic flowchart where the sequential steps of the bioinformatics study in which DockAnalyse might be used are described.