Are protein-protein interfaces special regions on a protein’s surface?
Open accessAbstract
Protein-protein interactions (PPIs) are involved in many cellular processes. Experimentally obtained protein quaternary structures provide the location of protein-protein interfaces, the surface region of a given protein that interacts with another. These regions are termed half-interfaces (HIs). Canonical HIs cover roughly one third of a protein’s surface and were found to have more hydrophobic residues than the non-interface surface region. In addition, the classical view of protein HIs was that there are a few (if not one) HIs per protein that are structurally and chemically unique. However, on average, a given protein interacts with at least a dozen others. This raises the question of whether they use the same or other HIs. By copying HIs from monomers with the same folds in solved quaternary structures, we introduce the concept of geometric HIs (HIs whose geometry has a significant match to other known interfaces) and show that on average they cover three quarters of a protein’s surface. We then demonstrate that in some cases, these geometric HI could result in real physical interactions (which may or may not be biologically relevant). The composition of the new HIs is on average more charged compared to most known ones, suggesting that the current protein interface database is biased towards more hydrophobic, possibly more obligate, complexes. Finally, our results provide evidence for interface fuzziness and PPI promiscuity. Thus, the classical view of unique, well defined HIs needs to be revisited as HIs are another example of coarse-graining that is used by nature.
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The structural space of protein-protein interfaces is small (<1000 structurally distinct interfaces), with nothing special about protein-protein interfaces.
“In practice, the structural space of protein–protein interfaces is small (<1000 structurally distinct interfaces),41,42 with nothing special about protein–protein interfaces.43”
From AlphaFold 2: Why It Works and Its Implications for Understanding the Relationships of Protein Sequence, Structure, and Function (2021) · cites this paper as [43]
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Cites
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs
Altschul, S. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.17.3389 · Cited by 73,302 · see citing works
VMD: visual molecular dynamics
Humphrey, W., Dalke, A., & Schulten, K. (1996) · Journal of Molecular Graphics · doi:10.1016/0263-7855(96)00018-5 · Cited by 66,952 · see citing works
Berman, H. M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.235 · Cited by 40,196 · see citing works
Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences
Li, W.-Z., & Godzik, A. (2006) · Bioinform. · doi:10.1093/bioinformatics/btl158 · Cited by 10,994 · see citing works
Amino acid substitution matrices from protein blocks.
Henikoff, S., & Henikoff, J. G. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.22.10915 · Cited by 6,218 · see citing works
Divergence measures based on the Shannon entropy
Lin, J.-H. (1991) · IEEE Transactions on Information Theory · doi:10.1109/18.61115 · Cited by 5,877 · see citing works
TM-align: a protein structure alignment algorithm based on the TM-score
Zhang, Y. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki524 · Cited by 3,774 · see citing works
HADDOCK: A Protein−Protein Docking Approach Based on Biochemical or Biophysical Information
Dominguez, C., Boelens, R., & Bonvin, A. M. J. J. (2003) · Journal of the American Chemical Society · doi:10.1021/ja026939x · Cited by 3,187 · see citing works
Anatomy of hot spots in protein interfaces
Bogan, A. A., & Thorn, K. S. (1998) · Journal of Molecular Biology · doi:10.1006/jmbi.1998.1843 · Cited by 1,988 · see citing works
ZDOCK server: interactive docking prediction of protein–protein complexes and symmetric multimers
Pierce, B. G., Wiehe, K. J., Hwang, H., Kim, B., Vreven, T., & Weng, Z. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu097 · Cited by 1,767 · see citing works
Protein Structure Prediction Using Rosetta
Rohl, C. A., Strauss, C. E. M., Misura, K. M. S., & Baker, D. A. (2004) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(04)83004-0 · Cited by 1,711 · see citing works
A Proteome-Scale Map of the Human Interactome Network
Rolland, T., Taşan, M., Charloteaux, B., Pevzner, S. J., Zhong, Q., Sahni, N., Yi, S. S., Lemmens, I. H., Fontanillo, C., Mosca, R., et al. (2014) · Cell · doi:10.1016/j.cell.2014.10.050 · Cited by 1,342 · see citing works
How significant is a protein structure similarity with TM-score = 0.5?
Xu, J., & Zhang, Y. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq066 · Cited by 1,142 · see citing works
Predicting protein–protein interactions based only on sequences information
Shen, J., Zhang, J., Luo, X., Zhu, W., Yu, K., Chen, K., Li, Y., & Jiang, H. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607879104 · Cited by 996 · see citing works
Diversity of protein–protein interactions
Nooren, I. M. A., & Thornton, J. (2003) · EMBO Journal · doi:10.1093/emboj/cdg359 · Cited by 942 · see citing works
An empirical framework for binary interactome mapping
Venkatesan, K., Rual, J.-F. M., Vázquez, A., Stelzl, U., Lemmens, I. H., Hirozane-Kishikawa, T., Hao, T., Zenkner, M., Xin, X., Goh, K. I., et al. (2008) · Nature Methods · doi:10.1038/nmeth.1280 · Cited by 907 · see citing works
Estimating the size of the human interactome
Stumpf, M. P. H., Thorne, T., de Silva, E., Stewart, R., An, H. J., Lappé, M., & Wiuf, C. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708078105 · Cited by 827 · see citing works
A simple physical model for binding energy hot spots in protein–protein complexes
Kortemme, T., & Baker, D. A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202485799 · Cited by 801 · see citing works
CAPRI: A Critical Assessment of PRedicted Interactions
Janin, J., Henrick, K., Moult, J., Eyck, L. T., Sternberg, M. J. E., Vajda, S., Vakser, I., & Wodak, S. J. (2003) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.10381 · Cited by 703 · see citing works
Principles of Protein−Protein Interactions: What are the Preferred Ways For Proteins To Interact?
Keskin, O., Gursoy, A., Ma, B., & Nussinov, R. (2008) · Chemical Reviews · doi:10.1021/cr040409x · Cited by 697 · see citing works
COFACTOR: an accurate comparative algorithm for structure-based protein function annotation
Roy, A., Yang, J., & Zhang, Y. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks372 · Cited by 695 · see citing works
Predicting functionally important residues from sequence conservation
Capra, J. A., & Singh, M. (2007) · Bioinformatics · doi:10.1093/bioinformatics/btm270 · Cited by 693 · see citing works
Analysis of protein-protein interaction sites using surface patches 1 1Edited by G.Von Heijne
Jones, S., & Thornton, J. M. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.1234 · Cited by 603 · see citing works
Structural Characterisation and Functional Significance of Transient Protein–Protein Interactions
Nooren, I., & Thornton, J. M. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)01281-0 · Cited by 587 · see citing works
Keskin, O., Ma, B., & Nussinov, R. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.10.077 · Cited by 519 · see citing works
Prediction of protein-protein interaction sites using patch analysis 1 1Edited by G. von Heijne
Jones, S., & Thornton, J. M. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.1233 · Cited by 426 · see citing works
Thorn, K. S., & Bogan, A. A. (2001) · Bioinformatics · doi:10.1093/bioinformatics/17.3.284 · Cited by 403 · see citing works
How complete are current yeast and human protein-interaction networks?
Hart, T., Ramani, A. K., & Marcotte, E. M. (2006) · Genome biology · doi:10.1186/gb-2006-7-11-120 · Cited by 402 · see citing works
Automated structure prediction of weakly homologous proteins on a genomic scale
Zhang, Y., & Skolnick, J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0305695101 · Cited by 344 · see citing works
Self-citationInterrogating protein interaction networks through structural biology
Aloy, P., & Russell, R. B. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.092147999 · Cited by 342 · see citing works
HIPPIE: Integrating Protein Interaction Networks with Experiment Based Quality Scores
Schaefer, M. H., Fontaine, J., Vinayagam, A., Porras, P., Wanker, E. E., & Andrade-Navarro, M. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031826 · Cited by 334 · see citing works
A threading-based method (FINDSITE) for ligand-binding site prediction and functional annotation
Brylinski, M., & Skolnick, J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707684105 · Cited by 333 · see citing works
Self-citationAn efficient library for parallel ray tracing and animation
Stone, J. E. (1998) · Cited by 307 · see citing works
Tunçbağ, N., Gürsoy, A., Nussinov, R., & Keskin, Ö. (2011) · Nature Protocols · doi:10.1038/nprot.2011.367 · Cited by 264 · see citing works
Lu, L. J., Lu, H. J., & Skolnick, J. (2002) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.10222 · Cited by 240 · see citing works
Self-citationHow Well Can We Understand Large-Scale Protein Motions Using Normal Modes of Elastic Network Models?
Yang, L., Song, G., & Jernigan, R. L. (2007) · Biophysical Journal · doi:10.1529/biophysj.106.095927 · Cited by 206 · see citing works
Baspinar, A., Cukuroglu, E., Nussinov, R., Keskin, Ö., & Gürsoy, A. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku397 · Cited by 201 · see citing works
On the origin and highly likely completeness of single-domain protein structures
Zhang, Y., Hubner, I. A., Arakaki, A. K., Shakhnovich, E., & Skolnick, J. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509379103 · Cited by 197 · see citing works
Self-citationProtein-Protein Complex Structure Predictions by Multimeric Threading and Template Recombination
Mukherjee, S., & Zhang, Y. (2011) · Structure · doi:10.1016/j.str.2011.04.006 · Cited by 174 · see citing works
Prediction of Protein–Protein Interaction Sites in Sequences and 3D Structures by Random Forests
Šikić, M., Tomić, S., & Vlahoviček, K. (2009) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000278 · Cited by 173 · see citing works
Protein interface conservation across structure space
Zhang, Q. C., Petrey, D., Norel, R., & Honig, B. H. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1005894107 · Cited by 156 · see citing works
Development of unified statistical potentials describing protein-protein interactions.
Lu, H., Lu, L., & Skolnick, J. (2003) · Biophysical Journal · doi:10.1016/s0006-3495(03)74997-2 · Cited by 144 · see citing works
Self-citationGao, M., & Skolnick, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1012820107 · Cited by 139 · see citing works
Self-citationComprehensive prediction of drug-protein interactions and side effects for the human proteome
Zhou, H., Gao, M., & Skolnick, J. (2015) · Scientific Reports · doi:10.1038/srep11090 · Cited by 138 · see citing works
Self-citationAPoc: large-scale identification of similar protein pockets
Gao, M., & Skolnick, J. (2013) · Bioinformatics · doi:10.1093/bioinformatics/btt024 · Cited by 125 · see citing works
Self-citationThe PDB is a Covering Set of Small Protein Structures
Kihara, D., & Skolnick, J. (2003) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.10.027 · Cited by 120 · see citing works
Self-citationInsights into disease-associated mutations in the human proteome through protein structural analysis
Gao, M., Zhou, H., & Skolnick, J. (2015) · Structure · doi:10.1016/j.str.2015.03.028 · Cited by 113 · see citing works
Self-citationPrediction of Protein-Protein Interaction Sites by Random Forest Algorithm with mRMR and IFS
Li, B., Feng, K., Chen, L., Huang, T., & Cai, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0043927 · Cited by 111 · see citing works
FINDSITE: a combined evolution/structure-based approach to protein function prediction
Skolnick, J., & Bryliński, M. (2009) · Briefings in Bioinformatics · doi:10.1093/bib/bbp017 · Cited by 106 · see citing works
Self-citationGuharoy, M., & Chakrabarti, P. (2010) · BMC Bioinformatics · doi:10.1186/1471-2105-11-286 · Cited by 102 · see citing works
Gao, M., & Skolnick, J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117768109 · Cited by 99 · see citing works
Self-citationTowards a detailed atlas of protein–protein interactions
Mosca, R., Pons, T., Ceol, A. G. M., Valencia, A., & Aloy, P. (2013) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2013.07.005 · Cited by 91 · see citing works
Challenges for the prediction of macromolecular interactions
Wass, M. N., David, A., & Sternberg, M. J. E. (2011) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2011.03.013 · Cited by 88 · see citing works
The continuity of protein structure space is an intrinsic property of proteins
Skolnick, J., Arakaki, A. K., Lee, S. Y., & Bryliński, M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907683106 · Cited by 83 · see citing works
Self-citationM-TASSER: An Algorithm for Protein Quaternary Structure Prediction
Chen, H., & Skolnick, J. (2008) · Biophysical Journal · doi:10.1529/biophysj.107.114280 · Cited by 68 · see citing works
Self-citationInterplay of physics and evolution in the likely origin of protein biochemical function
Skolnick, J., & Gao, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300011110 · Cited by 62 · see citing works
Self-citationAlgorithmic approaches to protein-protein interaction site prediction
Aumentado‐Armstrong, T., Istrate, B., & Murgita, R. A. (2015) · Algorithms for Molecular Biology · doi:10.1186/s13015-015-0033-9 · Cited by 62 · see citing works
HIPPIE: a high-throughput identification pipeline for promoter interacting enhancer elements
Hwang, Y.-C., Lin, C., Valladares, O., Malamon, J. S., Kuksa, P. P., Zheng, Q., Gregory, B. D., & Wang, L. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu801 · Cited by 52 · see citing works
Probing the origin of tubulin rigidity with molecular simulations
Dima, R. I., & Joshi, H. V. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806113105 · Cited by 48 · see citing works
Prescont: Predicting protein‐protein interfaces utilizing four residue properties
Zellner, H., Staudigel, M., Trenner, T., Bittkowski, M., Wolowski, V., Icking, C., & Merkl, R. (2011) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.23172 · Cited by 47 · see citing works
Predicting protein interface residues using easily accessible on-line resources
Maheshwari, S., & Bryliński, M. (2015) · Briefings in Bioinformatics · doi:10.1093/bib/bbv009 · Cited by 46 · see citing works
Park, J.-K., Jernigan, R. L., & Wu, Z. (2013) · Bulletin of Mathematical Biology · doi:10.1007/s11538-012-9797-y · Cited by 42 · see citing works
Bohnuud, T., Kozakov, D., & Vajda, S. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003872 · Cited by 27 · see citing works
Building and assessing atomic models of proteins from structural templates: Learning and benchmarks
Vallat, B. K., Pillardy, J., Májek, P., et al. (2009) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.22401 · Cited by 26 · see citing works
DOCK/PIERR: Web Server for Structure Prediction of Protein–Protein Complexes
Viswanath, S., Ravikant, D. V. S., & Elber, R. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-0366-5_14 · Cited by 26 · see citing works
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- Authors
- Tonddast-Navaei, S., & Skolnick, J.
- Affiliations
- Georgia Institute of Technology Center for the Study of Systems Biology, School of Biology, , 250 14th Street N.W., Atlanta, Georgia 30318, USA
- Georgia Institute of Technology (US)
- Venue
- The Journal of Chemical Physics
- Publisher
- AIP Publishing
- Published
- 2015-12-15
- Volume
- 143
- Issue
- 24
- Pages
- 243149-243149
- ISSN
- 0021-9606 (ISSN-L)
- 1089-7690
- PMC
- PMC4684567
- OpenAlex
- W2219859606
- Cited by
- 31
- References
- 65
- Citations by year
- 2024: 5 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 1 · 2019: 2 · 2018: 6 · 2017: 1 · 2016: 1 · 2015: 1
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Chemical Physics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Foundation for the National Institutes of Health (GM-37408)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- protein-protein interfaces, protein-protein interaction, protein surface, quaternary structure, interface geometry, hydrophobicity
- MeSH terms
- Binding Sites, Humans, Models, Molecular, Protein Binding, Proteins, Surface Properties, Protein Structure, Quaternary, Protein Interaction Domains and Motifs
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