Substitutions of individual amino acids in proteins may be under very different evolutionary restraints depending on their structural and functional roles. The Environment Specific Substitution Table (ESST) describes the pattern of substitutions in terms of amino acid location within elements of secondary structure, solvent accessibility, and the existence of hydrogen bonds between side chains and neighbouring amino acid residues. Clearly amino acids that have very different local environments in their functional state compared to those in the protein analysed will give rise to inconsistencies in the calculation of amino acid substitution tables. Here, we describe how the calculation of ESSTs can be improved by discarding the functional residues from the calculation of substitution tables. Four categories of functions are examined in this study: protein-protein interactions, protein-nucleic acid interactions, protein-ligand interactions, and catalytic activity of enzymes. Their contributions to residue conservation are measured and investigated. We test our new ESSTs using the program CRESCENDO, designed to predict functional residues by exploiting knowledge of amino acid substitutions, and compare the benchmark results with proteins whose functions have been defined experimentally. The new methodology increases the Z-score by 98% at the active site residues and finds 16% more active sites compared with the old ESST. We also find that discarding amino acids responsible for protein-protein interactions helps in the prediction of those residues although they are not as conserved as the residues of active sites. Our methodology can make the substitution tables better reflect and describe the substitution patterns of amino acids that are under structural restraints only.

UNLABELLED: Protein Structural Interactome map (PSIMAP) is a global interaction map that describes domain-domain and protein-protein interaction information for known Protein Data Bank structures. It calculates the Euclidean distance to determine interactions between possible pairs of structural domains in proteins. PSIbase is a database and file server for protein structural interaction information calculated by the PSIMAP algorithm. PSIbase also provides an easy-to-use protein domain assignment module, interaction navigation and visual tools. Users can retrieve possible interaction partners of their proteins of interests if a significant homology assignment is made with their query sequences. AVAILABILITY: http://psimap.org and http://psibase.kaist.ac.kr/

BACKGROUND: Most proteins function by interacting with other molecules. Their interaction interfaces are highly conserved throughout evolution to avoid undesirable interactions that lead to fatal disorders in cells. Rational drug discovery includes computational methods to identify the interaction sites of lead compounds to the target molecules. Identifying and classifying protein interaction interfaces on a large scale can help researchers discover drug targets more efficiently. DESCRIPTION: We introduce a large-scale protein domain interaction interface database called InterPare http://interpare.net. It contains both inter-chain (between chains) interfaces and intra-chain (within chain) interfaces. InterPare uses three methods to detect interfaces: 1) the geometric distance method for checking the distance between atoms that belong to different domains, 2) Accessible Surface Area (ASA), a method for detecting the buried region of a protein that is detached from a solvent when forming multimers or complexes, and 3) the Voronoi diagram, a computational geometry method that uses a mathematical definition of interface regions. InterPare includes visualization tools to display protein interior, surface, and interaction interfaces. It also provides statistics such as the amino acid propensities of queried protein according to its interior, surface, and interface region. The atom coordinates that belong to interface, surface, and interior regions can be downloaded from the website. CONCLUSION: InterPare is an open and public database server for protein interaction interface information. It contains the large-scale interface data for proteins whose 3D-structures are known. As of November 2004, there were 10,583 (Geometric distance), 10,431 (ASA), and 11,010 (Voronoi diagram) entries in the Protein Data Bank (PDB) containing interfaces, according to the above three methods. In the case of the geometric distance method, there are 31,620 inter-chain domain-domain interaction interfaces and 12,758 intra-chain domain-domain interfaces.