Proteins are the most important class of molecules in a cell. Most proteins function by interacting with other molecules, especially other proteins. The interactions among proteins are highly regulated and tightly conserved throughout evolution, [1, 2] mainly because unnecessary or unsatisfactory interaction (misinteraction) triggered by random mutations can lead to molecular dysfunction. Therefore, interaction interface regions are under pressure from natural selection and are more conserved [3] compared to other exposed non-interface regions of proteins. Protein “structural interactomics” to map all the protein domain interactions is becoming increasingly important as more complete genome sequences are made available [4–7]. Now scientists can map the whole human interactome bioinformatically [8], using ever-increasing experimental data coming from methods such as yeast two-hybrid analysis. Consequently, a higher resolution molecular interaction analysis is also becoming more important.
Since the 1970s, there has been much effort to determine the principles of protein-protein recognition. Pioneers in the field of protein-protein interaction, such as Chothia and Janin [9], have studied the physical and chemical properties of protein interaction sites that contribute to the recognition processes. Colman et al. [10, 11] focused on electrostatic and shape complementarity of interaction interfaces using EC (Electrostatic Complementarity) and shape correlation index, respectively. Argos [12] studied interfaces between protein subunits or protein domains. He not only investigated the physicochemical properties of protein interfaces, but also tried to understand the geometric features of protein interfaces using a spline function [13, 14]. Jones and Thornton [15] introduced a surface patch method to find out the parameters that contribute to the process of protein-protein interaction. Chakrabarti and Janin [16, 17] investigated the structure of interface region by dissecting it into core and rim based on different solvent accessibility. They also addressed the chemical properties of each region.
Recently, there has been a new trend in the study of protein interfaces. Several groups have introduced computational geometric and topology methods for the study of protein interfaces. Most importantly, the Voronoi diagram [18, 19, 23] has been used to study interfaces of protein complexes. As early as 1974, Richards [20, 21] first introduced the Voronoi diagram as an application for protein structure study, although not specifically as an interface analysis tool.
Despite all the efforts to unveil the underlying principles of protein-protein interaction for over 30 years, there has not been much progress at the fundamental level since the research by Chothia and Janin [9]. The interface data derived from different approaches are not well maintained or widely shared amongst scientists. Fortunately, with the help of faster X-ray crystallography and NMR in structural biology, there has been an increase in the number of known three-dimensional protein structures. This 3D structure information is a good source of data for the study of protein interfaces.
Here, we introduce a large-scale protein interaction interface database called InterPare (http://interpare.net or http://psimap.org). InterPare presents interfaces between protein domains identified by three methods. First, the interface is detected by calculating the geometric distance between subunits of multidomain proteins or protein complexes in the PDB [22, 27]. In the second approach, buried protein regions are identified by calculating the accessible surface area (ASA) when they form a complex or an aggregate with other subunits or domains. These buried regions can be accessible to water when they are in a free subunit or one domain state. Finally, interfaces are defined by a geometric and topological approach using the Voronoi diagram [18, 19, 23]. InterPare presents protein interfaces defined by the Voronoi diagram. The interface structure of queried proteins, in the context of the whole protein configuration, can be viewed with three different molecular viewers on the results page. They are the Chime [24], Jmol [25], and InterFacer [26]. InterPare also provides the atomic coordinate files for protein surface, interior, and interface for further analysis.
