Identification and Analysis of Binding Site Residues in Protein-Protein Complexes
We have developed an energy based approach for identifying the binding sites and important residues for binding in protein-protein complexes. We found that the residues and residuepairs with charged and aromatic side chains are important for binding. These residues influence to form cation-¤Ç, electrostatic and aromatic interactions. Our observation has been verified with the experimental binding specificity of protein-protein complexes and found good agreement with experiments. The analysis on surrounding hydrophobicity reveals that the binding residues are less hydrophobic than non-binding sites, which suggests that the hydrophobic core are important for folding and stability whereas the surface seeking residues play a critical role in binding. Further, the propensity of residues in the binding sites of receptors and ligands, number of medium and long-range contacts, and influence of neighboring residues will be discussed.
Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1060603Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 1082
 Ofran Y, Rost B, Analysing six types of protein-protein interfaces. J Mol Biol 2003, 325: 377-387.
 Chakrabarti P, Janin J Dissecting protein-protein recognition sites. Proteins 2002, 47: 334-343.
 Guharoy M, Chakrabarti Conservation and relative importance of residues across protein-protein interfaces. P Proc Natl Acad Sci U S A 2005, 102: 15447-15452.
 Ma B, Elkayam T, Wolfson H, Nussinov R Protein-protein interactions: structurally conserved residues distinguish between binding sites and exposed protein surfaces. Proc Natl Acad Sci U S A 2003, 100: 5772- 5777.
 Sheinerman FB, Honig B On the role of electrostatic interactions in the design of protein-protein interfaces. J Mol Biol 2002, 318: 161-177.
 Kortemme T, Baker D A simple physical model for binding energy hot spots in protein-protein complexes. Proc Natl Acad Sci U S A 2002, 99: 14116-14121.
 Kundrotas PJ, Alexov E Electrostatic properties of protein-protein complexes Biophys J 2006, 91: 1724-1736.
 Ofran Y, Rost B. Protein-protein interaction hotspots carved into sequences. PLoS Comput Biol. 2007; 3: e119.
 Aung Z, Tan SH, Ng SK, Tan KL. PPiClust: efficient clustering of 3D protein-protein interaction interfaces. J Bioinform Comput Biol. 2008; 6: 415-33.
 Urakubo Y, Ikura T, Ito N. Crystal structural analysis of protein-protein interactions drastically destabilized by a single mutation Protein Sci. 2008; 17: 1055-65.
 Lensink MF, Méndez R. Recognition-induced conformational changes in protein-protein docking Curr Pharm Biotechnol. 2008; 9: 77-86.
 Shoemaker BA, Panchenko AR. Deciphering protein-protein interactions. Part I. Experimental techniques and databases PLoS Comput Biol. 2007; 3: e42
 Shoemaker BA, Panchenko AR. Deciphering protein-protein interactions. Part II. Computational methods to predict protein and domain interaction partners PLoS Comput Biol. 2007; 3: e43.
 Keskin O, Gursoy A, Ma B, Nussinov R. Principles of protein-protein interactions: what are the preferred ways for proteins to interact? Chem Rev. 2008; 108: 1225-1244.
 Keskin O, Ma B, Rogale K, Gunasekaran K, Nussinov R. Proteinprotein interactions: organization, cooperativity and mapping in a bottom-up systems biology approach. Phys. Biol. 2005, 2, S24-35
 Jones S, Thornton JM. Prediction of protein-protein interaction sites using patch analysis J Mol Biol 1997, 272: 133-143.
 Sikić M, Tomić S, Vlahovicek K. Prediction of protein-protein interaction sites in sequences and 3D structures by random forests. PLoS Comput Biol. 2009; 5: e1000278.
 Shulman-Peleg A, Shatsky M, Nussinov R, Wolfson HJ. Nucleic Acids Res. 2008; 36: W260-264.
 Ertekin A, Nussinov R, Haliloglu T. Association of putative concave protein-binding sites with the fluctuation behavior of residues.Protein Sci. 2006; 15: 2265-2277
 Fariselli P, Pazos F, Valencia A, Casadio R Prediction of protein-- protein interaction sites in heterocomplexes with neural networks. Eur J Biochem 2002, 269: 1356-1361.
 Koike A, Takagi T Prediction of protein-protein interaction sites using support vector machines.Protein Eng Des Sel 2004, 17: 165-173.
 Res I, Mihalek I, Lichtarge O. An evolution based classifier for prediction of protein interfaces without using protein structures Bioinformatics. 2005; 21: 2496-501
 Ofran Y, Rost B. ISIS: interaction sites identified from sequence. Bioinformatics. 2007;23(2):e13-6
 Li W, Keeble AH, Giffard C, James R, Moore GR, Kleanthous C. Highly discriminating protein-protein interaction specificities in the context of a conserved binding energy hotspot J Mol Biol. 2004; 337: 743-59
 Keskin O, Tsai CJ, Wolfson H, Nussinov R. A new, structurally nonredundant, diverse data set of protein-protein interfaces and its implications Protein Sci. 2004; 13:1043-55.
 Glaser F, Steinberg DM, Vakser IA, Ben-Tal N. Residue frequencies and pairing preferences at protein-protein interfaces Proteins. 2001; 43: 89- 102.
 Berman H, Henrick K, Nakamura H, Markley JL. The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data Nucleic Acids Res. 2007; 35: D301-303.
 Needleman SB, Wunsch CD. A general method applicable to the search for similarities in the amino acid sequence of two proteins. J Mol Biol. 1970; 48: 443-453.
 Cornell,W.D.; Cieplak, P.; Bayly,C. I.; Gould, I. R.;Merz, K.M., Jr.; Ferguson,D.M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J.W.; Kollman, P. A. 1995. A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J Am Chem Soc 1995, 117, 5179- 5197.
 Pichierri F, Aida M, Gromiha MM, Sarai A. Free-energy maps of baseamino acid interactions in protein-DNA recognition. J. Amer. Chem. Soc. 1999, 121, 6152-6157.
 Gromiha MM, Yokota K, Fukui K. Energy based approach for understanding the recognition mechanism in protein-protein complexes. Mol. Biosystems, DOI: 10.1039/B904161N.
 Kumar MD, Gromiha MM. PINT: protein-protein interactions thermodynamic database. Nucleic Acids Res. 2006; 34: D195-8.
 Eletr ZM, Kuhlman B. Sequence determinants of E2-E6AP binding affinity and specificity J Mol Biol. 2007; 369: 419-28
 Zhang JL, Simeonowa I, Wang Y, Sebald W. The high-affinity interaction of human IL-4 and the receptor alpha chain is constituted by two independent binding clusters. J Mol Biol. 2002; 315: 399-407
 Kiel C, Serrano L, Herrmann C. A detailed thermodynamic analysis of ras/effector complex interfaces. J Mol Biol. 2004; 340: 1039-58.
 Manavalan P, Ponnuswamy PK. Hydrophobic character of amino acid residues in globular proteins. Nature. 1978;275(5681):673-4.
 Ponnuswamy PK. Hydrophobic characteristics of folded proteins. Prog Biophys Mol Biol. 1993;59(1):57-103.
 Nozaki Y, Tanford C. The solubility of amino acids and two glycine peptides in aqueous ethanol and dioxane solutions. Establishment of a hydrophobicity scale. J Biol Chem. 1971;246(7):2211-7.
 Jones DD. Amino acid properties and side-chain orientation in proteins: a cross correlation approach. J Theor Biol 1975;50:167-183.
 Gromiha MM, Selvaraj S. Inter-residue interactions in protein folding and stability. Prog Biophys Mol Biol. 2004;86(2):235-77.