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Protein complexes and functional modules in molecular networks.

ABSTRACT: Proteins, nucleic acids, and small molecules form a dense network of molecular interactions in a cell. Molecules are nodes of this network, and the interactions between them are edges. The architecture of molecular networks can reveal important principles of cellular organization and function, similarly to the way that protein structure tells us about the function and organization of a protein. Computational analysis of molecular networks has been primarily concerned with node degree [Wagner, A. & Fell, D. A. (2001) Proc. R. Soc. London Ser. B 268, 1803-1810; Jeong, H., Tombor, B., Albert, R., Oltvai, Z. N. & Barabasi, A. L. (2000) Nature 407, 651-654] or degree correlation [Maslov, S. & Sneppen, K. (2002) Science 296, 910-913], and hence focused on single/two-body properties of these networks. Here, by analyzing the multibody structure of the network of protein-protein interactions, we discovered molecular modules that are densely connected within themselves but sparsely connected with the rest of the network. Comparison with experimental data and functional annotation of genes showed two types of modules: (i) protein complexes (splicing machinery, transcription factors, etc.) and (ii) dynamic functional units (signaling cascades, cell-cycle regulation, etc.). Discovered modules are highly statistically significant, as is evident from comparison with random graphs, and are robust to noise in the data. Our results provide strong support for the network modularity principle introduced by Hartwell et al. [Hartwell, L. H., Hopfield, J. J., Leibler, S. & Murray, A. W. (1999) Nature 402, C47-C52], suggesting that found modules constitute the "building blocks" of molecular networks.

SUBMITTER: Spirin V

PROVIDER: S-EPMC218723 | biostudies-literature | 2003 Oct

REPOSITORIES: biostudies-literature

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Protein complexes and functional modules in molecular networks.

Spirin Victor V Mirny Leonid A LA

Proceedings of the National Academy of Sciences of the United States of America 20030929 21

Proteins, nucleic acids, and small molecules form a dense network of molecular interactions in a cell. Molecules are nodes of this network, and the interactions between them are edges. The architecture of molecular networks can reveal important principles of cellular organization and function, similarly to the way that protein structure tells us about the function and organization of a protein. Computational analysis of molecular networks has been primarily concerned with node degree [Wagner, A. ...[more]

PMID: 14517352

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Project description:BackgroundEscherichia coli always plays an important role in microbial research, and it has been a benchmark model for the study of molecular mechanisms of microorganisms. Molecular complexes, operons, and functional modules are valuable molecular functional domains of E. coli. The identification of protein complexes and functional modules of E. coli is essential to reveal the principles of cell organization, process, and function. At present, many studies focus on the detection of E. coli protein complexes based on experimental methods. However, based on the large-scale proteomics data set of E. coli, the simultaneous prediction of protein complexes and functional modules, especially the comparative analysis of them is relatively less.ResultsIn this study, the Edge Label Propagate Algorithm (ELPA) of the complex biological network was used to predict the protein complexes and functional modules of two high-quality PPI networks of E. coli, respectively. According to the gold standard protein complexes and function annotations provided by EcoCyc dataset, most protein modules predicted in the two datasets matched highly with real protein complexes, cellular processes, and biological functions. Some novel and significant protein complexes and functional modules were revealed based on ELPA. Moreover, through a comparative analysis of predicted complexes with corresponding functional modules, we found the protein complexes were significantly overlapped with corresponding functional modules, and almost all predicted protein complexes were completely covered by one or more functional modules. Finally, on the same PPI network of E. coli, ELPA was compared with a well-known protein module detection method (MCL) and we found that the performance of ELPA and MCL is comparable in predicting protein complexes.ConclusionsIn this paper, a link clustering method was used to predict protein complexes and functional modules in PPI networks of E. coli, and the correlation between them was compared, which could help us to understand the molecular functional units of E. coli better.

Project description:It is widely believed that the modular organization of cellular function is reflected in a modular structure of molecular networks. A common view is that a "module" in a network is a cohesively linked group of nodes, densely connected internally and sparsely interacting with the rest of the network. Many algorithms try to identify functional modules in protein-interaction networks (PIN) by searching for such cohesive groups of proteins. Here, we present an alternative approach independent of any prior definition of what actually constitutes a "module". In a self-consistent manner, proteins are grouped into "functional roles" if they interact in similar ways with other proteins according to their functional roles. Such grouping may well result in cohesive modules again, but only if the network structure actually supports this. We applied our method to the PIN from the Human Protein Reference Database (HPRD) and found that a representation of the network in terms of cohesive modules, at least on a global scale, does not optimally represent the network's structure because it focuses on finding independent groups of proteins. In contrast, a decomposition into functional roles is able to depict the structure much better as it also takes into account the interdependencies between roles and even allows groupings based on the absence of interactions between proteins in the same functional role. This, for example, is the case for transmembrane proteins, which could never be recognized as a cohesive group of nodes in a PIN. When mapping experimental methods onto the groups, we identified profound differences in the coverage suggesting that our method is able to capture experimental bias in the data, too. For example yeast-two-hybrid data were highly overrepresented in one particular group. Thus, there is more structure in protein-interaction networks than cohesive modules alone and we believe this finding can significantly improve automated function prediction algorithms.

Dataset Information

Protein complexes and functional modules in molecular networks.

Publications

Protein complexes and functional modules in molecular networks.

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