Cellular function is widely believed to be organized in a modular fashion. On all scales and at all levels of complexity, relatively independent sub-units perform relatively independent sub-tasks of biological function. This functional modularity must be reflected in the topology of molecular networks. But how a functional module should be represented in an interaction network is an open question. In protein-interaction networks (PIN), one can identify a protein-complex as a module on a small scale, i.e. modules are understood as densely linked, resp. interacting, groups of proteins, that are only sparsely interacting with the rest of the network.
In this contribution, we show that extrapolating this concept of cohesively linked clusters of proteins as modules to the scale of the entire PIN inevitable misses important and functionally relevant structure inherent in the network. As an alternative, we introduce a novel way of decomposing a network into functional roles and show that this represents network structure and function more efficiently. This finding should have a profound impact on all module assisted methods of protein function prediction and should shed new light on how functional modules can be represented in molecular interaction networks in general.
In this paper, we consider the statistical analysis of a protein interaction network. We propose a Bayesian model that uses a hierarchy of probabilistic assumptions about the way proteins interact with one another in order to: (i) identify the number of non-observable functional modules; (ii) estimate the degree of membership of proteins to modules; and (iii) estimate typical interaction patterns among the functional modules themselves. Our model describes large amount of (relational) data using a relatively small set of parameters that we can reliably estimate with an efficient inference algo…
Disease-causing mutations usually change the interacting partners of mutant proteins. In this article, we propose that the biological consequences of mutation are directly related to the alteration of corresponding protein protein interaction networks (PPIN). Mutation of Huntingtin (HTT) which causes Huntington's disease (HD) and mutations to TP53 which is associated with different cancers are studied as two example cases. We construct the PPIN of wild type and mutant proteins separately and identify the structural modules of each of the networks. The functional role of these modules are then …
The architecture of the network of protein-protein physical interactions in Saccharomyces cerevisiae is exposed through the combination of two complementary theoretical network measures, betweenness centrality and `Q-modularity'. The yeast interactome is characterized by well-defined topological modules connected via a small number of inter-module protein interactions. Should such topological inter-module connections turn out to constitute a form of functional coordination between the modules, we speculate that this coordination is occurring typically in a pair-wise fashion, rather than by way…
We present a method that compares the protein interaction networks of two species to detect functionally similar (conserved) protein modules between them. The method is based on an algorithm we developed to identify matching subgraphs between two graphs. Unlike previous network comparison methods, our algorithm has provable guarantees on correctness and efficiency. Our algorithm framework also admits quite general connectivity and local matching criteria that define when two subgraphs match and constitute a conserved module. We apply our method to pairwise comparisons of the yeast protein netw…
Cellular networks undergo rearrangements during stress and diseases. In un-stressed state the yeast protein-protein interaction network (interactome) is highly compact, and the centrally organized modules have a large overlap. During stress several original modules became more separated, and a number of novel modules also appear. A few basic functions, such as the proteasome preserve their central position. However, several functions with high energy demand, such the cell-cycle regulation loose their original centrality during stress. A number of key stress-dependent protein complexes, such as…
Biological networks provide insight into the complex organization of biological processes in a cell at the system level. They are an effective tool for understanding the comprehensive map of functional interactions, finding the functional modules and pathways. Reconstruction and comparative analysis of these networks provide useful information to identify functional modules, prioritization of disease causing genes and also identification of drug targets. The talk will consist of two parts. I will discuss several methods for protein-protein interaction network alignment and investigate their pr…
Summary: Most cellular tasks are performed not by individual proteins, but by groups of functionally associated proteins, often referred to as modules. In a protein assocation network modules appear as groups of densely interconnected nodes, also called communities or clusters. These modules often overlap with each other and form a network of their own, in which nodes (links) represent the modules (overlaps). We introduce CFinder, a fast program locating and visualizing overlapping, densely interconnected groups of nodes in undirected graphs, and allowing the user to easily navigate between th…
The so-called Mixed Feedback Loop (MFL) is a small two-gene network where protein A regulates the transcription of protein B and the two proteins form a heterodimer. It has been found to be statistically over-represented in statistical analyses of gene and protein interaction databases and to lie at the core of several computer-generated genetic networks. Here, we propose and mathematically study a model of the MFL and show that, by itself, it can serve both as a bistable switch and as a clock (an oscillator) depending on kinetic parameters. The MFL phase diagram as well as a detailed descript…
Network analysis became a powerful tool in recent years. Heat shock is a well-characterized model of cellular dynamics. S. cerevisiae is an appropriate model organism, since both its protein-protein interaction network (interactome) and stress response at the gene expression level have been well characterized. However, the analysis of the reorganization of the yeast interactome during stress has not been investigated yet. We calculated the changes of the interaction-weights of the yeast interactome from the changes of mRNA expression levels upon heat shock. The major finding of our study is th…
Background: If biology is modular then clusters, or communities, of proteins derived using only protein interaction network structure should define protein modules with similar biological roles. We investigate the link between biological modules and network communities in yeast and its relationship to the scale at which we probe the network. Results: Our results demonstrate that the functional homogeneity of communities depends on the scale selected, and that almost all proteins lie in a functionally homogeneous community at some scale. We judge functional homogeneity using a novel test and th…
Network Medicine has improved the mechanistic understanding of disease, offering quantitative insights into disease mechanisms, comorbidities, and novel diagnostic tools and therapeutic treatments. Yet, most network-based approaches rely on a comprehensive map of protein-protein interactions, ignoring interactions mediated by non-coding RNAs (ncRNAs). Here, we systematically combine experimentally confirmed binding interactions mediated by ncRNA with protein-protein interactions, constructing the first comprehensive network of all physical interactions in the human cell. We find that the inclu…
We investigate the dynamics of the heterodimer autorepression loop (HAL), a small genetic module in which a protein A acts as an auto-repressor and binds to a second protein B to form a AB dimer. For suitable values of the rate constants the HAL produces pulses of A alternating with pulses of B. By means of analytical and numerical calculations, we show that the duration of A-pulses is extremely robust against variation of the rate constants while the duration of the B-pulses can be flexibly adjusted. The HAL is thus a minimal genetic module generating robust pulses with tunable duration an in…
The promise of discovering a functional blueprint of a cellular system from large-scale and high-throughput sequence and experimental data is predicated on the belief that the same top-down investigative approach that proved successful in other biological problems (e.g. DNA sequencing) will be as effective when it comes to inferring more complex intracellular processes. The results in this paper address this fundamental issue in the specific context of transcription regulatory networks. Although simple recurring regulatory motifs have been identified in the past, due to the size and complexity…
Semmelweis University（塞麦尔维斯大学）；Pharmahungary Group（Pharmahungary集团）；Earlham Institute（厄勒姆研究所）；Turbine Ltd（Turbine有限公司）；Dana Farber Cancer Institute（达纳法伯癌症研究所）；Northeastern University（东北大学）；Wigner Research Centre for Physics（维格纳物理研究中心）
Motivation: Network visualizations of complex biological datasets usually result in 'hairball' images, which do not discriminate network modules. Results: We present the EntOptLayout Cytoscape plug-in based on a recently developed network representation theory. The plug-in provides an efficient visualization of network modules, which represent major protein complexes in protein-protein interaction and signalling networks. Importantly, the tool gives a quality score of the network visualization by calculating the information loss between the input data and the visual representation showing a 3-…
During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here we review the links between disordered proteins and the associated networks, and describe the consequences of local, mesoscopic and global network disorder on changes in protein structure and dynamics. We introduce a new classification of protein networks into cumulus-type, i.e., those similar to puffy (white) clouds, and stratus-type, i.e., those similar to flat, dense (dark) low-lying clouds, and relate these network types to protein disorder dynamics and to differences in energ…
We describe a modular modelling approach permitting curation, updating, and distributed development of modules through joined community effort overcoming the problem of keeping a combinatorially exploding number of monolithic models up to date. For this purpose, the effects of genes and their mutated alleles on downstream components are modeled by composable, metadata-containing Petri net models organized in a database with version control, accessible through a web interface. Gene modules can be coupled to protein modules through mRNA modules by specific interfaces designed for the automatic, …
Glycosylation is a highly complex process to produce a diverse repertoire of cellular glycans that are attached to proteins and lipids. Glycans are involved in fundamental biological processes, including protein folding and clearance, cell proliferation and apoptosis, development, immune responses, and pathogenesis. One of the major types of glycans, N-linked glycans, is formed by sequential attachments of monosaccharides to proteins by a limited number of enzymes. Many of these enzymes can accept multiple N-linked glycans as substrates, thereby generating a large number of glycan intermediate…
In systems biology new ways are required to analyze the large amount of existing data on regulation of cellular processes. Recent work can be roughly classified into either dynamical models of well-described subsystems, or coarse-grained descriptions of the topology of the molecular networks at the scale of the whole organism. In order to bridge these two disparate approaches one needs to develop simplified descriptions of dynamics and topological measures which address the propagation of signals in molecular networks. Here, we consider the directed network of protein regulation in E. coli, ch…
Mutations in proteins can have deleterious effects on a protein's stability and function, which ultimately causes particular diseases. Genetically inherited muscular dystrophies (MDs) include several genetic diseases, which cause increasing weakness in muscles and disability to perform muscular functions progressively. Different types of mutations in the gene coding translates into defunct proteins cause different neuro-muscular diseases. Defunct protein interactions in human proteome may cause a stress to its neighboring proteins and its modules. We therefore aimed to understand the effects o…
PRING: Rethinking Protein-Protein Interaction Prediction from Pairs to Graphs
National University of Singapore（新加坡国立大学）；Shanghai Artificial Intelligence Laboratory（上海人工智能实验室）；Shanghai Innovation Institute（上海创新研究院）；Fudan University（复旦大学）；Westlake University（西湖大学）；Chinese University of Hong Kong（香港中文大学）；Xi’an Jiaotong University（西安交通大学）；Central South University（中南大学）；Shenzhen Loop Area Institute（深圳河套学院）
Corynebacterium glutamicum is a Gram-positive bacterium found in soil where the condition changes demand plasticity of the regulatory machinery. The study of such machinery at the global scale has been challenged by the lack of data integration. Here, we report three regulatory network models for C. glutamicum: strong (3040 interactions) constructed solely with regulations previously supported by directed experiments; all evidence (4665 interactions) containing the strong network, regulations previously supported by non-directed experiments, and protein-protein interactions with a direct effec…
We study how the dynamic equilibrium of the reversible protein-protein binding network in yeast Saccharomyces cerevisiae responds to large changes in abundances of individual proteins. The magnitude of shifts between free and bound concentrations of their immediate and more distant neighbors in the network is influenced by such factors as the network topology, the distribution of protein concentrations among its nodes, and the average binding strength. Our primary conclusion is that, on average, the effects of a perturbation are strongly localized and exponentially decay with the network dista…
A major part of membrane function is conducted by proteins, both integral and peripheral. Peripheral membrane proteins temporarily adhere to biological membranes, either to the lipid bilayer or to integral membrane proteins with non-covalent interactions. The aim of this study was to construct and analyze the interactions of the human plasma membrane peripheral proteins (peripherome hereinafter). For this purpose, we collected a dataset of peripheral proteins of the human plasma membrane. We also collected a dataset of experimentally verified interactions for these proteins. The interaction ne…
We study the explosive character of the percolation transition in a real-world network. We show that the emergence of a spanning cluster in the Human Protein Homology Network (H-PHN) exhibits similar features to an Achlioptas-type process and is markedly different from regular random percolation. The underlying mechanism of this transition can be described by slow-growing clusters that remain isolated until the later stages of the process, when the addition of a small number of links leads to the rapid interconnection of these modules into a giant cluster. Our results indicate that the evoluti…
With the advent of high-throughput wet lab technologies the amount of protein interaction data available publicly has increased substantially, in turn spurring a plethora of computational methods for in silico knowledge discovery from this data. In this paper, we focus on parameterized methods for modeling and solving complex computational problems encountered in such knowledge discovery from protein data. Specifically, we concentrate on three relevant problems today in proteomics, namely detection of lethal proteins, functional modules and alignments from protein interaction networks. We prop…
The p53 protein is well-known for its tumour suppressor function. The p53-MDM2 negative feedback loop constitutes the core module of a network of regulatory interactions activated under cellular stress. In normal cells, the level of p53 proteins is kept low by MDM2, i.e. MDM2 negatively regulates the activity of p53. In the case of DNA damage,the p53-mediated pathways are activated leading to cell cycle arrest and repair of the DNA. If repair is not possible due to excessive damage, the p53-mediated apoptotic pathway is activated bringing about cell death. In this paper, we give an overview of…
Renmin University of China（中国人民大学）；DP Technology（深势科技）
The prediction of protein-ligand binding affinity is of great significance for discovering lead compounds in drug research. Facing this challenging task, most existing prediction methods rely on the topological and/or spatial structure of molecules and the local interactions while ignoring the multi-level inter-molecular interactions between proteins and ligands, which often lead to sub-optimal performance. To solve this issue, we propose a novel global-local interaction (GLI) framework to predict protein-ligand binding affinity. In particular, our GLI framework considers the inter-molecular i…
Studies on the role of fluctuations in signal propagation and on gene regulation in monoclonal bacterial population have been extensively pursued based on the machinery of two-component system. The bacterial two-component system shows noise utilisation through its inherent plasticity. The fluctuations propagation takes place using the phosphotransfer module and the feedback mechanism during gene regulation. To delicately observe the noisy kinetics the generic cascade needs stochastic investigation at the mRNA and protein levels. To this end, we propose a theoretical framework to investigate th…
Diffusion-based network models are widely used for protein function prediction using protein network data and have been shown to outperform neighborhood- and module-based methods. Recent studies have shown that integrating the hierarchical structure of the Gene Ontology (GO) data dramatically improves prediction accuracy. However, previous methods usually either used the GO hierarchy to refine the prediction results of multiple classifiers, or flattened the hierarchy into a function-function similarity kernel. No study has taken the GO hierarchy into account together with the protein network a…
Experimental evidence suggests that epidermal growth factor receptor (EGFR)-mediated activation of the signaling protein phospholipase C gamma plays a critical role in a cancer cell's phenotypic decision to either proliferate or to migrate at a given point in time. Here, we present a novel three-dimensional multiscale agent-based model to simulate this cellular decision process in the context of a virtual brain tumor. Each tumor cell is equipped with an EGFR gene-protein interaction network module that also connects to a simplified cell cycle description. The simulation results show that over …
Topological network motifs represent functional relationships within and between regulatory and protein-protein interaction networks. Enriched motifs often aggregate into self-contained units forming functional modules. Theoretical models for network evolution by duplication-divergence mechanisms and for network topology by hierarchical scale-free networks have suggested a one-to-one relation between network motif enrichment and aggregation, but this relation has never been tested quantitatively in real biological interaction networks. Here we introduce a novel method for assessing the statist…
A variety of complex systems exhibit different types of relationships simultaneously that can be modeled by multiplex networks. A typical problem is to determine the community structure of such systems that, in general, depend on one or more parameters to be tuned. In this study we propose one measure, grounded on information theory, to find the optimal value of the relax rate characterizing Multiplex Infomap, the generalization of the Infomap algorithm to the realm of multilayer networks. We evaluate our methodology on synthetic networks, to show that the most representative community structu…
Background. Biological networks have growing importance for the interpretation of high-throughput "omics" data. Statistical and combinatorial methods allow to obtain mechanistic insights through the extraction of smaller subnetwork modules. Further enrichment analyses provide set-based annotations of these modules. Results. We present eXamine, a set-oriented visual analysis approach for annotated modules that displays set membership as contours on top of a node-link layout. Our approach extends upon Self Organizing Maps to simultaneously lay out nodes, links, and set contours. Conclusions. We …
Quantum Optimisation for Protein-Protein Interaction Network Alignment
University of Hamburg（汉堡大学）；Parity Quantum Computing Germany GmbH（帕里特量子计算德国有限公司）；Parity Quantum Computing GmbH（帕里特量子计算有限公司）；Institute for Theoretical Physics, University of Innsbruck（因斯布鲁克大学理论物理研究所）；Department of Mathematics and Computer Science, University of Southern Denmark（南丹麦大学数学与计算机科学系）
Biological networks have evolved to be highly functional within uncertain environments while remaining extremely adaptable. One of the main contributors to the robustness and evolvability of biological networks is believed to be their modularity of function, with modules defined as sets of genes that are strongly interconnected but whose function is separable from those of other modules. Here, we investigate the in silico evolution of modularity and robustness in complex artificial metabolic networks that encode an increasing amount of information about their environment while acquiring ubiqui…
The relationship between the regulatory design and the functionality of molecular networks is a key issue in biology. Modules and motifs have been associated to various cellular processes, thereby providing anecdotal evidence for performance based localization on molecular networks. To quantify structure-function relationship we investigate similarities of proteins which are close in the regulatory network of the yeast Saccharomyces Cerevisiae. We find that the topology of the regulatory network show weak remnants of its history of network reorganizations, but strong features of co-regulated p…
Cluster-based descriptions of biological networks have received much attention in recent years fostered by accumulated evidence of the existence of meaningful correlations between topological network clusters and biological functional modules. Several well-performing clustering algorithms exist to infer topological network partitions. However, due to respective technical idiosyncrasies they might produce dissimilar modular decompositions of a given network. In this contribution, we aimed to analyze how alternative modular descriptions could condition the outcome of follow-up network biology an…
The complexity of the cells can be described and understood by a number of networks such as protein-protein interaction, cytoskeletal, organelle, signalling, gene transcription and metabolic networks. All these networks are highly dynamic producing continuous rearrangements in their links, hubs, network-skeleton and modules. Here we describe the adaptation of cellular networks after various forms of stress causing perturbations, congestions and network damage. Chronic stress decreases link-density, decouples or even quarantines modules, and induces an increased competition between network hubs…
Summary: The ModuLand plug-in provides Cytoscape users an algorithm for determining extensively overlapping network modules. Moreover, it identifies several hierarchical layers of modules, where meta-nodes of the higher hierarchical layer represent modules of the lower layer. The tool assigns module cores, which predict the function of the whole module, and determines key nodes bridging two or multiple modules. The plug-in has a detailed JAVA-based graphical interface with various colouring options. The ModuLand tool can run on Windows, Linux, or Mac OS. We demonstrate its use on protein struc…
The protein p53 has a well established role in protecting genomic integrity in human cells. When DNA is damaged p53 induces the cell cycle arrest to prevent the transmission of the damage to cell progeny, triggers the production of proteins for DNA repair and ultimately calls for apoptosis. In particular, the p53-Mdm2 feedback loop seems to be the key circuit in this response of cells to damage. For many years, based on measurements over populations of cells it was believed that the p53-Mdm2 feedback loop was the responsible for the existence of damped oscillations in the levels of p53 and Mdm…
We propose a growing network model that consists of two tunable mechanisms: growth by merging modules which are represented as complete graphs and a fitness-driven preferential attachment. Our model exhibits the three prominent statistical properties are widely shared in real biological networks, for example gene regulatory, protein-protein interaction, and metabolic networks. They retain three power law relationships, such as the power laws of degree distribution, clustering spectrum, and degree-degree correlation corresponding to scale-free connectivity, hierarchical modularity, and disassor…
