BACKGROUND: Studying the patterns of protein-protein interactions (PPIs) is fundamental for understanding the structure and function of protein complexes. The exploration of the vast space of possible mutual configurations of interacting proteins and their contact zones is very time consuming and requires the proteomic expert knowledge. RESULTS: In this paper, we propose a novel tool containing a set of visual abstraction techniques for the guided exploration of PPI configuration space. It helps proteomic experts to select the most relevant configurations and explore their contact zones at different levels of detail. The system integrates a set of methods that follow and support the workflow of proteomics experts. The first visual abstraction method, the Matrix view, is based on customized interactive heat maps and provides the users with an overview of all possible residue-residue contacts in all PPI configurations and their interactive filtering. In this step, the user can traverse all input PPI configurations and obtain an overview of their interacting amino acids. Then, the models containing a particular pair of interacting amino acids can be selectively picked and traversed. Detailed information on the individual amino acids in the contact zones and their properties is presented in the Contact-Zone list-view. The list-view provides a comparative tool to rank the best models based on the similarity of their contacts to the template-structure contacts. All these techniques are interactively linked with other proposed methods, the Exploded view and the Open-Book view, which represent individual configurations in three-dimensional space. These representations solve the high overlap problem associated with many configurations. Using these views, the structural alignment of the best models can also be visually confirmed. CONCLUSIONS: We developed a system for the exploration of large sets of protein-protein complexes in a fast and intuitive way. The usefulness of our system has been tested and verified on several docking structures covering the three major types of PPIs, including coiled-coil, pocket-string, and surface-surface interactions. Our case studies prove that our tool helps to analyse and filter protein-protein complexes in a fraction of the time compared to using previously available techniques.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Informatics University of Bergen Bergen Norway

Faculty of Informatics Masaryk University Brno Czech Republic

Institute of Visual Computing and Human Centered Technology TU Wien Wien Austria

National Centre for Biomolecular Research Masaryk University Brno Czech Republic

Zobrazit více v PubMed

Gavin AC, Aloy P, Grandi P, Krause R, Boesche M, Marzioch M, Rau C, Jensen LJ, Bastuck S, Dumpelfeld B, Edelmann A, Heurtier MA, Hoffman V, Hoefert C, Klein K, Hudak M, Michon AM, Schelder M, Schirle M, Remor M, Rudi T, Hooper S, Bauer A, Bouwmeester T, Casari G, Drewes G, Neubauer G, Rick JM, Kuster B, Bork P, Russell RB, Superti-Furga G. Proteome survey reveals modularity of the yeast cell machinery. Nature. 2006;440(7084):631–6. doi: 10.1038/nature04532. PubMed DOI

Huang SY. Search strategies and evaluation in protein-protein docking: principles, advances and challenges. Drug Discov Today. 2014;19(8):1081–96. doi: 10.1016/j.drudis.2014.02.005. PubMed DOI

Malhotra S, Mathew OK, Sowdhamini R. DOCKSCORE: a webserver for ranking protein-protein docked poses. BMC Bioinformatics. 2015;16(1):1–6. doi: 10.1186/s12859-015-0572-6. PubMed DOI PMC

Jin L, Wang W, Fang G. Targeting protein-protein interaction by small molecules. Annu Rev Pharmacol Toxicol. 2014;54(1):435–56. doi: 10.1146/annurev-pharmtox-011613-140028. PubMed DOI

Lee CH, Varshney A. Scientific Visualization: The Visual Extraction of Knowledge from Data. Berlin: Springer; 2005. Computing and displaying intermolecular negative volume for docking.

Varshney A, Brooks Jr FP, Manocha D, Wright WV, Richardson DC. Proceedings of the 6th Conference on Visualization’95. Atlanta: IEEE Computer Society; 1995. Defining, computing, and visualizing molecular interfaces.

Ban YEA, Edelsbrunner H, Rudolph J. Interface surfaces for protein-protein complexes. J ACM (JACM) 2006;53(3):361–78. doi: 10.1145/1147954.1147957. DOI

Laskowski RA, Hutchinson GE, Michie AD, Wallace AC, Jones ML, Thornton JM. PDBsum: a web-based database of summaries and analyses of all PDB structures. Trends Biochem Sci. 1997;22(12):488–90. doi: 10.1016/S0968-0004(97)01140-7. PubMed DOI

Lex A, Streit M, Schulz H, Partl C, Schmalstieg D, Park PJ, Gehlenborg N. StratomeX: visual analysis of Large-Scale heterogeneous genomics data for cancer subtype characterization. Comput Graph Forum (EuroVis ’12) 2012;31(3):1175–84. doi: 10.1111/j.1467-8659.2012.03110.x. PubMed DOI PMC

Kozlikova B, Sebestova E, Sustr V, Brezovsky J, Strnad O, Daniel L, Bednar D, Pavelka A, Manak M, Bezdeka M, et al. Caver analyst 1.0: graphic tool for interactive visualization and analysis of tunnels and channels in protein structures. Bioinformatics. 2014;30(18):2684–5. doi: 10.1093/bioinformatics/btu364. PubMed DOI

Dominguez C, Boelens R, Bonvin AMJJ. HADDOCK: A protein-protein docking approach based on biochemical or biophysical information. J Am Chem Soc. 2003;125(7):1731–7. doi: 10.1021/ja026939x. PubMed DOI

Jimenez-Garcia B, Pons C, Fernandez-Recio J. pyDockWEB: a web server for rigid-body protein-protein docking using electrostatics and desolvation scoring. Bioinformatics. 2013;29(13):1698–9. doi: 10.1093/bioinformatics/btt262. PubMed DOI

Rao R, Card SK. Proceedings of the ACM SIGCHI Conference on Human Factors in Computing Systems (CHI ’94) Boston: ACM; 1994. The table lens: Merging graphical and symbolic representations in an interactive focus + context visualization for tabular information.

Shindyalov IN, Bourne PE. Protein structure alignment by incremental combinatorial extension (CE) of the optimal path. Protein Eng. 1998;11(9):739–47. doi: 10.1093/protein/11.9.739. PubMed DOI

Palecek JJ, Gruber S. Kite Proteins: a Superfamily of SMC/Kleisin Partners Conserved Across Bacteria, Archaea, and Eukaryotes. Structure. 2015;23(12):2183–90. doi: 10.1016/j.str.2015.10.004. PubMed DOI

Gligoris T, Lowe J. Structural Insights into Ring Formation of Cohesin and Related Smc Complexes. Trends Cell Biol. 2016;26(9):680–93. doi: 10.1016/j.tcb.2016.04.002. PubMed DOI PMC

Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. 4th edn. New York: Garland Science; 2002.

Zabrady K, Adamus M, Vondrova L, Liao C, Skoupilova H, Novakova M, Jurcisinova L, Alt A, Oliver AW, Lehmann AR, Palecek JJ. Chromatin association of the SMC5/6 complex is dependent on binding of its NSE3 subunit to DNA. Nucleic Acids Res. 2016;44(3):1064–79. doi: 10.1093/nar/gkv1021. PubMed DOI PMC

Doyle JM, Gao J, Wang J, Yang M, Potts PR. MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell. 2010;39(6):963–74. doi: 10.1016/j.molcel.2010.08.029. PubMed DOI PMC

Hudson JJ, Bednarova K, Kozakova L, Liao C, Guerineau M, Colnaghi R, Vidot S, Marek J, Bathula SR, Lehmann AR, Palecek J. Interactions between the Nse3 and Nse4 components of the SMC5-6 complex identify evolutionarily conserved interactions between MAGE and EID Families. PLoS ONE. 2011;6(2):17270. doi: 10.1371/journal.pone.0017270. PubMed DOI PMC

Kozakova L, Vondrova L, Stejskal K, Charalabous P, Kolesar P, Lehmann AR, Uldrijan S, Sanderson CM, Zdrahal Z, Palecek JJ. The melanoma-associated antigen 1 (MAGEA1) protein stimulates the E3 ubiquitin-ligase activity of TRIM31 within a TRIM31-MAGEA1-NSE4 complex. Cell Cycle. 2015;14(6):920–30. doi: 10.1080/15384101.2014.1000112. PubMed DOI PMC

van der Crabben SN, Hennus MP, McGregor GA, Ritter DI, Nagamani SCS, Wells OS, Harakalová M, Chinn IK, Alt A, Vondrová L, Hochstenbach R, van Montfrans JM, Terheggen-Lagro SW, van Lieshout S, van Roosmalen MJ, Renkens I, Duran K, Nijman IJ, Kloosterman WP, Hennekam E, Orange JS, van Hasselt PM, Wheeler DA, Palecek JJ, Lehmann AR, Oliver AW, Pearl LH, Plon SE, Murray JM, van Haaften G. Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease. J Clin Investig. 2016;126(8):2881–92. doi: 10.1172/JCI82890. PubMed DOI PMC

Gligoris TG, Scheinost JC, Burmann F, Petela N, Chan KL, Uluocak P, Beckouet F, Gruber S, Nasmyth K, Lowe J. Closing the cohesin ring: structure and function of its Smc3-kleisin interface. Science. 2014;346(6212):963–7. doi: 10.1126/science.1256917. PubMed DOI PMC

Woo JS, Lim JH, Shin HC, Suh MK, Ku B, Lee KH, Joo K, Robinson H, Lee J, Park SY, Ha NC, Oh BH. Structural studies of a bacterial condensin complex reveal ATP-dependent disruption of intersubunit interactions. Cell. 2009;136(1):85–96. doi: 10.1016/j.cell.2008.10.050. PubMed DOI

Role of Nse1 Subunit of SMC5/6 Complex as a Ubiquitin Ligase

A role of the Nse4 kleisin and Nse1/Nse3 KITE subunits in the ATPase cycle of SMC5/6

A Single Conserved Amino Acid Residue as a Critical Context-Specific Determinant of the Differential Ability of Mdm2 and MdmX RING Domains to Dimerize