Protein–Protein Interactions: The Structural Foundation of Life Complexity

The amazing variety of protein functions are often covered by protein complexes, so understanding protein–protein interactions means coming deeply into the functional role of proteins in life. In the last years, the investigation of protein–protein interactions has become central in many fields, spanning from molecular biology to pharmacology. In this article, we present a state of the art of methods for such investigation, along with perspectives of applications. We stressed the multiscale nature of approaches, longing from genome-wide analysis to the detailed study of protein–protein interface on single residues. The most innovative approaches, based on complex network theory, shed a very bright light on future trends for protein–protein applications on drug design and on molecular therapy for diseases where protein association plays a pivotal role (misfolding). Key Concepts Protein–protein interactions underlie several physiological mechanisms. The analysis of protein–protein interfaces is crucial to quantify protein complex stability. Hotspot residues provide the largest contribution to protein–protein binding energy. Experimental methods point to identify hotspots and quantify binding energy. Molecular docking allows a fine analysis of protein–protein interface. Network-based approaches clarify the multiscale nature of protein–protein interactions. Keywords: protein–protein interactions; hotspots; protein–protein interface; computational methods; network pharmacology; drug design

[1]  Péter Csermely,et al.  The efficiency of multi-target drugs: the network approach might help drug design. , 2004, Trends in pharmacological sciences.

[2]  Daniele Santoni,et al.  Proteins as Sponges: A Statistical Journey along Protein Structure Organization Principles , 2012, J. Chem. Inf. Model..

[3]  John P. Overington,et al.  How many drug targets are there? , 2006, Nature Reviews Drug Discovery.

[4]  D. Scott,et al.  Small molecules, big targets: drug discovery faces the protein–protein interaction challenge , 2016, Nature Reviews Drug Discovery.

[5]  S. Pongor,et al.  A Network-Based Target Overlap Score for Characterizing Drug Combinations: High Correlation with Cancer Clinical Trial Results , 2015, PloS one.

[6]  A. Bogan,et al.  Anatomy of hot spots in protein interfaces. , 1998, Journal of molecular biology.

[7]  S. Jones,et al.  Principles of protein-protein interactions. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Shifman,et al.  Cold Spots in Protein Binding. , 2016, Trends in biochemical sciences.

[9]  B. Snel,et al.  Conservation of gene order: a fingerprint of proteins that physically interact. , 1998, Trends in biochemical sciences.

[10]  Peter Csermely,et al.  Perturbation Centrality and Turbine: A Novel Centrality Measure Obtained Using a Versatile Network Dynamics Tool , 2013, PloS one.

[11]  R. Guimerà,et al.  Classes of complex networks defined by role-to-role connectivity profiles. , 2007, Nature physics.

[12]  C S Raman,et al.  Isothermal titration calorimetry of protein-protein interactions. , 1999, Methods.

[13]  S. Pongor,et al.  Multiple weak hits confuse complex systems: a transcriptional regulatory network as an example. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[14]  Ruth Nussinov,et al.  Disordered proteins and network disorder in network descriptions of protein structure, dynamics and function: hypotheses and a comprehensive review. , 2012 .

[15]  Ilya A Vakser,et al.  Protein-protein docking: from interaction to interactome. , 2014, Biophysical journal.

[16]  L. Di Paola,et al.  Molecular features of interaction between VEGFA and anti-angiogenic drugs used in retinal diseases: a computational approach , 2015, Front. Pharmacol..

[17]  Francesco Saverio Pavone,et al.  Optical methods in the study of protein-protein interactions. , 2010, Advances in experimental medicine and biology.

[18]  Pedro Alexandrino Fernandes,et al.  Computational alanine scanning mutagenesis—An improved methodological approach , 2007, J. Comput. Chem..

[19]  Ashkan Golshani,et al.  Computational methods for predicting protein-protein interactions. , 2008, Advances in biochemical engineering/biotechnology.

[20]  Alessandro Giuliani,et al.  Protein contact network topology: a natural language for allostery. , 2015, Current opinion in structural biology.

[21]  J. Joung,et al.  A bacterial two-hybrid selection system for studying protein-DNA and protein-protein interactions. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Gabriele Ausiello,et al.  MINT: the Molecular INTeraction database , 2006, Nucleic Acids Res..

[23]  Delia Cabrera DeBuc,et al.  Fractal-based analysis of optical coherence tomography data to quantify retinal tissue damage , 2014, BMC Bioinformatics.

[24]  Gary D Bader,et al.  BIND--The Biomolecular Interaction Network Database. , 2001, Nucleic acids research.

[25]  Solène Grosdidier,et al.  Identification of hot-spot residues in protein-protein interactions by computational docking , 2008, BMC Bioinformatics.

[26]  Burkhard Rost,et al.  Protein–Protein Interaction Hotspots Carved into Sequences , 2007, PLoS Comput. Biol..

[27]  Ozlem Keskin,et al.  PRISM: protein-protein interaction prediction by structural matching. , 2008, Methods in molecular biology.

[28]  D. Leitner.  Energy flow in proteins. , 2008, Annual review of physical chemistry.

[29]  R. Nussinov,et al.  Protein–protein interactions: organization, cooperativity and mapping in a bottom-up Systems Biology approach , 2005, Physical biology.

[30]  A. Hopkins.  Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[31]  O. Keskin,et al.  Predicting Protein-Protein Interactions from the Molecular to the Proteome Level. , 2016, Chemical reviews.

[32]  R. Nussinov,et al.  Protein–protein interactions: Structurally conserved residues distinguish between binding sites and exposed protein surfaces , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[33]  G. Rose,et al.  The Levinthal paradox of the interactome , 2011, Protein science : a publication of the Protein Society.

[34]  S. Mangani.  Disruption of Protein-Protein Interfaces: In Search of New Inhibitors , 2013 .

[35]  Ruth Nussinov,et al.  Structure and dynamics of molecular networks: A novel paradigm of drug discovery. A comprehensive review , 2012, Pharmacology & therapeutics.

[36]  B. Snel,et al.  Comparative assessment of large-scale data sets of protein–protein interactions , 2002, Nature.

[37]  A. Finazzi-Agro’,et al.  The importance of being dimeric , 2004, The FEBS journal.

[38]  A. Giuliani,et al.  Protein contact networks: an emerging paradigm in chemistry. , 2013, Chemical reviews.

[39]  Robert B. Russell,et al.  InterPreTS: protein Interaction Prediction through Tertiary Structure , 2003, Bioinform..

[40]  Patrick Aloy,et al.  Interrogating protein interaction networks through structural biology , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. She,et al.  Protein microarrays to detect protein-protein interactions using red and green fluorescent proteins. , 2002, Analytical biochemistry.

[42]  Sachdev S Sidhu,et al.  Comprehensive and Quantitative Mapping of Energy Landscapes for Protein-Protein Interactions by Rapid Combinatorial Scanning*♦ , 2006, Journal of Biological Chemistry.

[43]  Alexander Dömling.  Protein-Protein Interactions in Drug Discovery: DOEMLING:PROTEIN INTERAC O-BK , 2013 .