Protein—protein binding supersites

The lack of a deep understanding of how proteins interact remains an important roadblock in advancing efforts to identify binding partners and uncover the corresponding regulatory mechanisms of the functions they mediate. Understanding protein-protein interactions is also essential for designing specific chemical modifications to develop new reagents and therapeutics. We explored the hypothesis of whether protein interaction sites serve as generic biding sites for non-cognate protein ligands, just as it has been observed for small-molecule-binding sites in the past. Using extensive computational docking experiments on a test set of 241 protein complexes, we found that indeed there is a strong preference for non-cognate ligands to bind to the cognate binding site of a receptor. This observation appears to be robust to variations in docking programs, types of non-cognate protein probes, sizes of binding patches, relative sizes of binding patches and full-length proteins, and the exploration of obligate and non-obligate complexes. The accuracy of the docking scoring function appears to play a role in defining the correct site. The frequency of interaction of unrelated probes recognizing the binding interface was utilized in a simple prediction algorithm that showed accuracy competitive with other state of the art methods.

[1]  Jaime Prilusky,et al.  Automated analysis of interatomic contacts in proteins , 1999, Bioinform..

[2]  A. Fiser,et al.  ProtLID, a Residue-Based Pharmacophore Approach to Identify Cognate Protein Ligands in the Immunoglobulin Superfamily. , 2016, Structure.

[3]  P. Chakrabarti,et al.  Conservation and relative importance of residues across protein-protein interfaces , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[4]  P. Hajduk,et al.  Druggability indices for protein targets derived from NMR-based screening data. , 2005, Journal of medicinal chemistry.

[5]  Alan Wee-Chung Liew,et al.  Sequence‐based prediction of protein–peptide binding sites using support vector machine , 2016, J. Comput. Chem..

[6]  Z. Weng,et al.  Binding interface prediction by combining protein–protein docking results , 2014, Proteins.

[7]  Andrej Sali,et al.  Localization of protein‐binding sites within families of proteins , 2005, Protein science : a publication of the Protein Society.

[8]  B. Rost,et al.  Analysing six types of protein-protein interfaces. , 2003, Journal of molecular biology.

[9]  Song Liu,et al.  Protein binding site prediction using an empirical scoring function , 2006, Nucleic acids research.

[10]  D. Ringe.  What makes a binding site a binding site? , 1995, Current opinion in structural biology.

[11]  Barry Honig,et al.  Structural bioinformatics of the interactome. , 2014, Annual review of biophysics.

[12]  Zhiping Weng,et al.  Accelerating Protein Docking in ZDOCK Using an Advanced 3D Convolution Library , 2011, PloS one.

[13]  Lukasz A. Kurgan,et al.  Review and comparative assessment of sequence‐based predictors of protein‐binding residues , 2018, Briefings Bioinform..

[14]  B. Honig,et al.  Structure-based prediction of protein-protein interactions on a genome-wide scale , 2012, Nature.

[15]  Alan Wee-Chung Liew,et al.  Structure‐based prediction of protein‐ peptide binding regions using Random Forest , 2018, Bioinform..

[16]  Alessandra Carbone,et al.  Identification of protein interaction partners and protein-protein interaction sites. , 2008, Journal of molecular biology.

[17]  David R Westhead,et al.  Asymmetric mutation rates at enzyme–inhibitor interfaces: Implications for the protein–protein docking problem , 2003, Protein science : a publication of the Protein Society.

[18]  I. Vakser,et al.  Main-chain complementarity in protein-protein recognition. , 1996, Protein engineering.

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

[20]  Thomas C. Northey,et al.  IntPred: a structure-based predictor of protein–protein interaction sites , 2017, Bioinform..

[21]  P. Goodford.  A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[22]  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.

[23]  N. Ben-Tal,et al.  Residue frequencies and pairing preferences at protein–protein interfaces , 2001, Proteins.

[24]  Barry Honig,et al.  On the role of electrostatic interactions in the design of protein-protein interfaces. , 2002, Journal of molecular biology.

[25]  Ian H. Witten,et al.  Data mining: practical machine learning tools and techniques, 3rd Edition , 1999 .

[26]  Raphael A. G. Chaleil,et al.  Updates to the Integrated Protein-Protein Interaction Benchmarks: Docking Benchmark Version 5 and Affinity Benchmark Version 2. , 2015, Journal of molecular biology.

[27]  A. Thomas,et al.  A fast method to predict protein interaction sites from sequences. , 2000, Journal of molecular biology.

[28]  Sarah A. Teichmann,et al.  Principles of protein-protein interactions , 2002, ECCB.

[29]  Daniel R. Caffrey,et al.  Are protein–protein interfaces more conserved in sequence than the rest of the protein surface? , 2004, Protein science : a publication of the Protein Society.

[30]  Haruki Nakamura,et al.  The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data , 2006, Nucleic Acids Res..

[31]  A. McCoy,et al.  Electrostatic complementarity at protein/protein interfaces. , 1997, Journal of molecular biology.

[32]  Alfonso Valencia,et al.  Progress and challenges in predicting protein-protein interaction sites , 2008, Briefings Bioinform..

[33]  E. Katchalski‐Katzir,et al.  Molecular surface recognition: determination of geometric fit between proteins and their ligands by correlation techniques. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Alexandre M J J Bonvin,et al.  Are scoring functions in protein-protein docking ready to predict interactomes? Clues from a novel binding affinity benchmark. , 2010, Journal of proteome research.

[35]  P. Linsley,et al.  Rational Development of LEA29Y (belatacept), a High‐Affinity Variant of CTLA4‐Ig with Potent Immunosuppressive Properties , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[36]  N. Grishin,et al.  The subunit interfaces of oligomeric enzymes are conserved to a similar extent to the overall protein sequences , 1994, Protein science : a publication of the Protein Society.

[37]  J. Thornton,et al.  Diversity of protein–protein interactions , 2003, The EMBO journal.

[38]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[39]  M. Karplus,et al.  Functionality maps of binding sites: A multiple copy simultaneous search method , 1991, Proteins.

[40]  A. Bulpitt,et al.  Insights into protein-protein interfaces using a Bayesian network prediction method. , 2006, Journal of molecular biology.

[41]  András Fiser,et al.  Identifying functionally informative evolutionary sequence profiles , 2018, Bioinform..

[42]  Dima Kozakov,et al.  Fragment-based identification of druggable 'hot spots' of proteins using Fourier domain correlation techniques , 2009, Bioinform..

[43]  Andras Fiser,et al.  Trends in structural coverage of the protein universe and the impact of the Protein Structure Initiative , 2014, Proceedings of the National Academy of Sciences.

[44]  Hongbo Zhu,et al.  NOXclass: prediction of protein-protein interaction types , 2006, BMC Bioinformatics.

[45]  A. Fiser.  Protein structure modeling in the proteomics era , 2004, Expert review of proteomics.

[46]  C. Chothia,et al.  The atomic structure of protein-protein recognition sites. , 1999, Journal of molecular biology.

[47]  M. Karplus,et al.  Multiple copy simultaneous search and construction of ligands in binding sites: application to inhibitors of HIV-1 aspartic proteinase. , 1993, Journal of medicinal chemistry.

[48]  Xiaolong Wang,et al.  Protein-protein interaction site prediction based on conditional random fields , 2007, Bioinform..

[49]  Juliette Martin,et al.  Arbitrary protein−protein docking targets biologically relevant interfaces , 2012, BMC biophysics.

[50]  Zhiping Weng,et al.  Performance of ZDOCK and ZRANK in CAPRI rounds 13–19 , 2010, Proteins.

[51]  M J Sternberg,et al.  Supersites within superfolds. Binding site similarity in the absence of homology. , 1998, Journal of molecular biology.

[52]  David A. Lee,et al.  CATH: comprehensive structural and functional annotations for genome sequences , 2014, Nucleic Acids Res..

[53]  Arun K. Ramani,et al.  Protein interaction networks from yeast to human. , 2004, Current opinion in structural biology.

[54]  Alessandra Carbone,et al.  Great interactions: How binding incorrect partners can teach us about protein recognition and function , 2016, Proteins.

[55]  R. Abagyan,et al.  Identification of protein-protein interaction sites from docking energy landscapes. , 2004, Journal of molecular biology.

[56]  R. Russell,et al.  The relationship between sequence and interaction divergence in proteins. , 2003, Journal of molecular biology.

[57]  Aleksey A. Porollo,et al.  Prediction‐based fingerprints of protein–protein interactions , 2006, Proteins.

[58]  Dima Kozakov,et al.  Analysis of protein binding sites by computational solvent mapping. , 2012, Methods in molecular biology.