- Budapest, Budapest fovaros, Hungary
Peter Csermely
Semmelweis University, LINK Group, Medical Chemistry, Faculty Member
ModuLand plug-in for Cytoscape: extensively overlapping modules, community centrality and their use in biological networks
Photo-acoustic stimulation increases the amount of 70 kDa heat shock protein (Hsp70) in human whole saliva. A pilot study a a a a b,
There is a widening recognition that cancer cells are products of complex developmental processes. Carcinogenesis and metastasis formation are increasingly described as systems-level, network phenomena. Here we propose that malignant... more
There is a widening recognition that cancer cells are products of complex developmental processes. Carcinogenesis and metastasis formation are increasingly described as systems-level, network phenomena. Here we propose that malignant transformation is a two-phase process, where an initial increase of system plasticity is followed by a decrease of plasticity at late stages of carcinogenesis as a model of cellular learning. We describe the hallmarks of increased system plasticity of early, tumor initiating cells, such as increased noise, entropy, conformational and phenotypic plasticity, physical deformability, cell heterogeneity and network rearrangements. Finally, we argue that the large structural changes of molecular networks during cancer development necessitate a rather different targeting strategy in early and late phase of carcinogenesis. Plastic networks of early phase cancer development need a central hit, while rigid networks of late stage primary tumors or established meta...
Creativity and talent is promoted by specific network structures and positions. Creative nodes are positioned in the overlap of many network communities, and have a highly dynamic and independent status. Creative nodes appear at the... more
Creativity and talent is promoted by specific network structures and positions. Creative nodes are positioned in the overlap of many network communities, and have a highly dynamic and independent status. Creative nodes appear at the molecular, cellular and social levels, and are supported by the rest of the network. As examples of talent support networks the Hungarian research student movement, its international network, the Network of Youth Excellence, the Hungarian talent support network (helping more than 25,000 talented people in the last two years) and the currently developing EU talent support network will be introduced. The establishment of a world-wide talent support network would uncover huge local talent reserves, would provide the best support to them, and by creating millions of novel creative node positions would magnify the talent-capacity of the whole Earth.
Research Interests: Psychology and Creativity
Cancer initiation and development are increasingly perceived as systems-level phenomena, where intra- and inter-cellular signaling networks of the ecosystem of cancer and stromal cells offer efficient methodologies for outcome prediction... more
Cancer initiation and development are increasingly perceived as systems-level phenomena, where intra- and inter-cellular signaling networks of the ecosystem of cancer and stromal cells offer efficient methodologies for outcome prediction and intervention design. Within this framework, RAS emerges as a 'contextual signaling hub', i.e. the final result of RAS activation or inhibition is determined by the signaling network context. Current therapies often 'train' cancer cells shifting them to a novel attractor, which has increased metastatic potential and drug resistance. The few therapy-surviving cancer cells are surrounded by massive cell death triggering a primordial adaptive and reparative general wound healing response. Overall, dynamic analysis of patient- and disease-stage specific intracellular and intercellular signaling networks may open new areas of anticancer therapy using multitarget drugs, drugs combinations, edgetic drugs, as well as help design 'gent...
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Our century has unprecedented new challenges, which need creative solutions and deep thinking. Contemplative, deep thinking became an “endangered species” in our rushing world of Tweets, elevator pitches, and fast decisions. Here, we... more
Our century has unprecedented new challenges, which need creative solutions and deep thinking. Contemplative, deep thinking became an “endangered species” in our rushing world of Tweets, elevator pitches, and fast decisions. Here, we describe how important aspects of both creativity and deep thinking can be understood as network phenomena of conceptual and social networks. “Creative nodes” occupy highly dynamic, boundary spanning positions in social networks. Creative thinking requires alternating plasticity-dominated and rigidity-dominated mind-sets, which can be helped by dynamically changing social network structures. In the closing section, we present three case studies which demonstrate the applications of the concept in the Hungarian research student movement, the Hungarian Templeton Program, and the Youth Platform of the European Talent Support Network. These examples show how talent support programs can mobilize the power of social networks to enhance creative, deliberative,...
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1. Recent Prog Horm Res. 1993;48:291-339. The insulin receptor and its substrate: molecular determinants of early events in insulin action. Kahn CR, White MF, Shoelson SE, Backer JM, Araki E, Cheatham B, Csermely P, Folli F, Goldstein BJ,... more
1. Recent Prog Horm Res. 1993;48:291-339. The insulin receptor and its substrate: molecular determinants of early events in insulin action. Kahn CR, White MF, Shoelson SE, Backer JM, Araki E, Cheatham B, Csermely P, Folli F, Goldstein BJ, Huertas P, et al. Joslin Diabetes Center, Department of Medicine Brigham and Women's Hospital, Boston, Massachusetts. PMID: 7680139 [PubMed - indexed for MEDLINE]. Publication Types: Research Support, Non-US Gov't; Research Support, US Gov't, PHS; Review. MeSH Terms. ...
Research Interests: Endocrinology, Biology, Medicine, Humans, Internal Medicine, and 14 moreMutagenesis, Insulin, Animals, Phosphotyrosine, Clinical Sciences, Insulin Receptor, Amino Acid Sequence, Tyrosine, Biochemistry and cell biology, Molecular Structure, Insulin Receptor Substrate, Molecular Sequence Data, Receptor Insulin, and Paediatrics and reproductive medicine
Research Interests: Biochemistry, Bioinformatics, Environmental Science, Developmental Biology, Climate Change, and 15 moreComputational Biology, Biotechnology, Cancer, Biology, Cell Cycle, Ecology, Drug Discovery, Astrophysics, Astronomy, DNA, Escherichia coli, Cell Signalling, Biological evolution, Environmental Conditions, and Earth Science
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Research Interests: Chemistry, Kinetics, Biological Chemistry, Biological Sciences, HSP, and 15 moreHumans, Mice, Animals, CHEMICAL SCIENCES, Cisplatin, Heat Shock Protein, Base Sequence, Cell Survival, Lactones, Benzoquinones, Membrane Fluidity, Hemolysis, Macrolides, Molecular Sequence Data, and Medical and Health Sciences
Research Interests: Chemistry, Biological Chemistry, Medicine, Biological Sciences, Cortisol, and 15 moreAnimals, Male, Biological, Glutathione, Endoplasmic Reticulum, Light, Enzyme, NADPH oxidase, CHEMICAL SCIENCES, Oxygen, Glutathione Reductase, Power Reduction, Nucleotides, hydrocortisone, and Medical and Health Sciences
Research Interests: Endocrinology, Medicine, Internal Medicine, Insulin, Animals, and 15 moreMale, Clinical Sciences, Rats, Public health systems and services research, Isoenzymes, Protein Expression, Body Weight, Enzyme activity, Streptozotocin, Diabetic Rat, Heart Ventricles, Binding Site, Left Ventricle, Ouabain, and Paediatrics and reproductive medicine
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Research Interests: Kinetics, Biology, Apoptosis, Medicine, Cellular Signalling, and 15 moreSomatostatin, Humans, Cell Death, Kinase inhibitor, Cyclic peptides, Mitogen Activated Protein Kinase, Epidermal Growth Factor, Neoplasms, Gel electrophoresis, Growth Factor, Antineoplastic Agents, Intracellular Signaling, Biochemistry and cell biology, Tyrosine Phosphorylation, and Mitogen- Activated Protein Kinases
Background Signaling networks in eukaryotes are made up of upstream and downstream subnetworks. The upstream subnetwork contains the intertwined network of signaling pathways, while the downstream regulatory part contains transcription... more
Background Signaling networks in eukaryotes are made up of upstream and downstream subnetworks. The upstream subnetwork contains the intertwined network of signaling pathways, while the downstream regulatory part contains transcription factors and their binding sites on the DNA as well as microRNAs and their mRNA targets. Currently, most signaling and regulatory databases contain only a subsection of this network, making comprehensive analyses highly time-consuming and dependent on specific data handling expertise. The need for detailed mapping of signaling systems is also supported by the fact that several drug development failures were caused by undiscovered cross-talk or regulatory effects of drug targets. We previously created a uniformly curated signaling pathway resource, SignaLink, to facilitate the analysis of pathway cross-talks. Here, we present SignaLink 2, which significantly extends the coverage and applications of its predecessor. Description We developed a novel conce...
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We have studied the effect of insulin stimulation on phosphotyrosine phosphatase (PTPase) activity in the well-differentiated rat hepatoma cell line Fao. PTPase activity was measured using a 32P-labeled peptide corresponding to the major... more
We have studied the effect of insulin stimulation on phosphotyrosine phosphatase (PTPase) activity in the well-differentiated rat hepatoma cell line Fao. PTPase activity was measured using a 32P-labeled peptide corresponding to the major site of insulin receptor autophosphorylation. Of the PTPase activity in Fao cells, 14% was in the cytosolic fraction, whereas 86% was in the particulate fraction; this latter fraction also had a 4-fold higher specific activity. Purification of the particulate fraction by lectin chromatography resulted in a 50% increase in specific activity, although this glycoprotein-rich fraction contained only 1.5% of the total activity. Both the cytosolic and particulate PTPase fractions were active toward the tyrosyl-phosphorylated insulin receptor in vitro. The activity of the particulate fraction but not the cytosolic fraction was inhibited by addition of a micromolar concentration of a phosphorylated peptide corresponding to residues 1142-1153 of the human insulin receptor sequence. By contrast, addition of the nonphosphorylated peptide even at millimolar concentration was without effect. Both PTPase fractions were inhibited by Zn+ at similar concentrations, whereas the cytosolic PTPase activity was 10-fold more sensitive to vanadate inhibition. Treatment of cells with 100 nM insulin increased PTPase activity in the particulate fraction by 40% and decreased activity in the cytosolic fraction by 35%. These effects occurred within 15 min and were half-maximal at 3-4 nM insulin. When assessed as total activity, the magnitude of the changes in PTPase activity in the particulate and cytosolic fractions could not be explained on the basis of a translocation of PTPases between the two pools.(ABSTRACT TRUNCATED AT 250 WORDS)
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Research Interests: Biology, Cell Cycle, Enzyme Inhibitors, Flavonoids, Cercopithecus aethiops, and 15 moreHumans, Animals, Cyclic peptides, Biochemical, Isoenzymes, MAPK, Cell Cycle Arrest, Antineoplastic Agents, Maleimides, Biochemistry and cell biology, Anticancer Drug, Cytostatic, Enzyme Induction, Cell Membrane, and Medical biochemistry and metabolomics
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Research Interests: Biology and Cell Biology
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The network paradigm is increasingly used to describe the dynamics of complex systems. Here we review the current results and propose future development areas in the assessment of perturbation waves, i.e. propagating structural changes in... more
The network paradigm is increasingly used to describe the dynamics of complex systems. Here we review the current results and propose future development areas in the assessment of perturbation waves, i.e. propagating structural changes in amino acid networks building individual protein molecules and in protein-protein interaction networks (interactomes). We assess the possibilities and critically review the initial attempts for the application of game theory to the often rather complicated process, when two protein molecules approach each other, mutually adjust their conformations via multiple communication steps and finally, bind to each other. We also summarize available data on the application of percolation theory for the prediction of amino acid network- and interactome-dynamics. Furthermore, we give an overview of the dissection of signals and noise in the cellular context of various perturbations. Finally, we propose possible applications of the reviewed methodologies in drug...
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Molecular processes of neuronal learning have been well-described. However, learning mechanisms of non-neuronal cells have not been fully understood at the molecular level. Here, we discuss molecular mechanisms of cellular learning,... more
Molecular processes of neuronal learning have been well-described. However, learning mechanisms of non-neuronal cells have not been fully understood at the molecular level. Here, we discuss molecular mechanisms of cellular learning, including conformational memory of intrinsically disordered proteins and prions, signaling cascades, protein translocation, RNAs (microRNA and lncRNA), and chromatin memory. We hypothesize that these processes constitute the learning of signaling networks and correspond to a generalized Hebbian learning process of single, non-neuronal cells, and discuss how cellular learning may open novel directions in drug design and inspire new artificial intelligence methods.
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We increasingly rely on the network approach to understand the complexity of cellular functions. Chaperones (heat shock proteins) are key "networkers", which have among their functions to sequester and repair damaged protein. In... more
We increasingly rely on the network approach to understand the complexity of cellular functions. Chaperones (heat shock proteins) are key "networkers", which have among their functions to sequester and repair damaged protein. In order to link the network approach and chaperones with the aging process, we first summarize the properties of aging networks suggesting a "weak link theory of aging". This theory suggests that age-related random damage primarily affects the overwhelming majority of the low affinity, transient interactions (weak links) in cellular networks leading to increased noise, destabilization and diversity. These processes may be further amplified by age-specific network remodelling and by the sequestration of weakly linked cellular proteins to protein aggregates of aging cells. Chaperones are weakly linked hubs [i.e., network elements with a large number of connections] and inter-modular bridge elements of protein-protein interaction, signalling a...
Research Interests: Biology, Mitochondria, Medicine, Neurodegenerative Diseases, Signal Transduction, and 15 moreMolecular chaperones, Protein-Protein Interaction, Humans, Protein Aggregation, Cellular Network, Proteins, Neurons, Regulatory Network, Aged, Stochastic Resonance, Targeted Therapy, Heat Shock Proteins, Heat Shock Protein, Protein- Protein interaction network analysis, and Medical and Health Sciences
Cooperation plays a key role in the evolution of complex systems. However, the level of cooperation extensively varies with the topology of agent networks in the widely used models of repeated games. Here we show that cooperation remains... more
Cooperation plays a key role in the evolution of complex systems. However, the level of cooperation extensively varies with the topology of agent networks in the widely used models of repeated games. Here we show that cooperation remains rather stable by applying the reinforcement learning strategy adoption rule, Q-learning on a variety of random, regular, small-word, scale-free and modular network models in repeated, multi-agent Prisoners Dilemma and Hawk-Dove games. Furthermore, we found that using the above model systems other long-term learning strategy adoption rules also promote cooperation, while introducing a low level of noise (as a model of innovation) to the strategy adoption rules makes the level of cooperation less dependent on the actual network topology. Our results demonstrate that long-term learning and random elements in the strategy adoption rules, when acting together, extend the range of network topologies enabling the development of cooperation at a wider range...
Research Interests: Computer Science, Algorithms, Physics, Game Theory, Reinforcement Learning, and 15 moreBiology, Medicine, Multidisciplinary, Learning, Complex System, Humans, Computer Simulation, Network evolution, Interpersonal Relations, PLoS one, Learning Strategies, Model System, Network Topology, Network Model, and Cooperative Behavior
Recent studies have demonstrated that network approaches are highly appropriate tools to understand the extreme complexity of the aging process. The generality of the network concept helps to define and study the aging of technological,... more
Recent studies have demonstrated that network approaches are highly appropriate tools to understand the extreme complexity of the aging process. The generality of the network concept helps to define and study the aging of technological, social networks and ecosystems, which may give novel concepts to cure age-related diseases. The current review focuses on the role of protein-protein interaction networks (interactomes) in aging. Hubs and inter-modular elements of both interactomes and signaling networks are key regulators of the aging process. Aging induces an increase in the permeability of several cellular compartments, such as the cell nucleus, introducing gross changes in the representation of network structures. The large overlap between aging genes and genes of age-related major diseases makes drugs which aid healthy aging promising candidates for the prevention and treatment of age-related diseases, such as cancer, atherosclerosis, diabetes and neurodegenerative disorders. We...
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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... more
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 that heat shock induced a significant decrease in both the overlaps and connections of yeast interactome modules. In agreement with this the weighted diameter of the yeast interactome had a 4.9-fold increase in heat shock. Several key proteins of the heat shock response became centers of heat shock-induced local communities, as well as bridges providing a residual connection of modules after heat...
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I hypothesize that re-occurring prior experience of complex systems mobilizes a fast response, whose attractor is encoded by their strongly connected network core. In contrast, responses to novel stimuli are often slow and require the... more
I hypothesize that re-occurring prior experience of complex systems mobilizes a fast response, whose attractor is encoded by their strongly connected network core. In contrast, responses to novel stimuli are often slow and require the weakly connected network periphery. Upon repeated stimulus, peripheral network nodes remodel the network core that encodes the attractor of the new response. This "core-periphery learning" theory reviews and generalizes the heretofore fragmented knowledge on attractor formation by neural networks, periphery-driven innovation and a number of recent reports on the adaptation of protein, neuronal and social networks. The coreperiphery learning theory may increase our understanding of signaling, memory formation, information encoding and decision-making processes. Moreover, the power of network periphery-related 'wisdom of crowds' inventing creative, novel responses indicates that deliberative democracy is a slow yet efficient learning st...
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Despite considerable progress in genome- and proteome-based high-throughput screening methods and rational drug design, the number of successful single target drugs did not increase appreciably during the past decade. Network models... more
Despite considerable progress in genome- and proteome-based high-throughput screening methods and rational drug design, the number of successful single target drugs did not increase appreciably during the past decade. Network models suggest that partial inhibition of a surprisingly small number of targets can be more efficient than the complete inhibition of a single target. This and the success stories of multi-target drugs and combinatorial therapies led us to suggest that systematic drug design strategies should be directed against multiple targets. We propose that the final effect of partial, but multiple drug actions might often surpass that of complete drug action at a single target. The future success of this novel drug design paradigm will depend not only on a new generation of computer models to identify the correct multiple hits and their multi-fitting, low-affinity drug candidates but also on more efficient in vivo testing.
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Robust systems, like the molecular networks of living cells are often resistant to single hits such as those caused by high-specificity drugs. Here we show that partial weakening of the Escherichia coli and Saccharomyces cerevisiae... more
Robust systems, like the molecular networks of living cells are often resistant to single hits such as those caused by high-specificity drugs. Here we show that partial weakening of the Escherichia coli and Saccharomyces cerevisiae transcriptional regulatory networks at a small number (3-5) selected nodes can have a greater impact than the complete elimination of a single selected node. In both cases, the targeted nodes have the greatest possible impact; still the results suggest that in some cases broad specificity compounds or multitarget drug therapies may be more effective than individual high-affinity, high-specificity ones. Multiple but partial attacks mimic well a number of in vivo scenarios and may be useful in the efficient modification of other complex systems.
Research Interests: Engineering, Biology, Transcription Factors, Medicine, Protein Engineering, and 10 moreSignal Transduction, Saccharomyces cerevisiae, Complex System, Computer Simulation, Mathematical Sciences, Escherichia coli, Physical sciences, Learning Theory and Modeling, Drug Therapy, and Gene Expression Regulation
Water molecules and molecular chaperones efficiently help the protein folding process. Here we describe their action in the context of the energy and topological networks of proteins. In energy terms water and chaperones were suggested to... more
Water molecules and molecular chaperones efficiently help the protein folding process. Here we describe their action in the context of the energy and topological networks of proteins. In energy terms water and chaperones were suggested to decrease the activation energy between various local energy minima smoothing the energy landscape, rescuing misfolded proteins from conformational traps and stabilizing their native structure. In kinetic terms water and chaperones may make the punctuated equilibrium of conformational changes less punctuated and help protein relaxation. Finally, water and chaperones may help the convergence of multiple energy landscapes during protein-macromolecule interactions. We also discuss the possibility of the introduction of protein games to narrow the multitude of the energy landscapes when a protein binds to another macromolecule. Both water and chaperones provide a diffuse set of rapidly fluctuating weak links (low affinity and low probability interaction...
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Here we present Translocatome, the first dedicated database of human translocating proteins. The core of the Translocatome database is the manually curated data set of 213 human translocating proteins listing the source of their... more
Here we present Translocatome, the first dedicated database of human translocating proteins. The core of the Translocatome database is the manually curated data set of 213 human translocating proteins listing the source of their experimental validation, several details of their translocation mechanism, their local compartmentalized interactome, as well as their involvement in signalling pathways and disease development. In addition, using the well-established and widely used gradient boosting machine learning tool, XGBoost, Translocatome provides translocation probability values for 13,066 human proteins identifying 1133 and 3268 high- and low-confidence translocating proteins, respectively. The database has user-friendly search options with a UniProt autocomplete quick search and advanced search for proteins filtered by their localization, UniProt identifiers, translocation likelihood or data complexity. Download options of search results, manually curated and predicted translocati...
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Single molecule and NMR measurements of protein dynamics increasingly uncover the complexity of binding scenarios. Here we describe an extended conformational selection model which embraces a repertoire of selection and adjustment... more
Single molecule and NMR measurements of protein dynamics increasingly uncover the complexity of binding scenarios. Here we describe an extended conformational selection model which embraces a repertoire of selection and adjustment processes. Induced fit can be viewed as a subset of this repertoire, whose contribution is affected by the bond-types stabilizing the interaction and the differences between the interacting partners. We argue that protein segments whose dynamics are distinct from the rest of the protein ('discrete breathers') can govern conformational transitions and allosteric propagation that accompany binding processes, and as such may be more sensitive to mutational events. Additionally, we highlight the dynamic complexity of binding scenarios as they relate to events such as aggregation and signalling, and the crowded cellular environment.
Research Interests: Bioinformatics, Physics, Chemistry, Protein Folding, Biotechnology, and 14 moreBiology, Protein Dynamics, Medicine, Single molecule, Signal Transduction, Biological Sciences, Humans, Model Selection, Animals, Proteins, CHEMICAL SCIENCES, Protein Conformation, Protein Binding, and Medical and Health Sciences
Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding... more
Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding drugs have side effects, as compared to those which have no reported side effects. Our results showed that in general, drug targets were better spreaders of perturbations than non-target proteins, and in particular, targets of drugs with side effects were also better spreaders of perturbations than targets of drugs having no reported side effects in human protein-protein interaction networks. Colorectal cancer-related proteins were good spreaders and had a high centrality, while type 2 diabetes-related proteins showed an average spreading efficiency and had an average centrality in the human interactome. Moreover, the interactome-distance between drug targets and disease-related proteins was higher in diabetes than in colorectal cancer. Our results ...
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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,... more
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 energy transmission processes. In the first class, there is limited overlap between the modules, which implies higher rigidity of the individual units; there the conformational changes can be described by an energy transfer mechanism. In the second class, the topology presents a compact structure with significant overlap between the modules; there the conformational changes can be described by multi...
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Analysis of network dynamics became a focal point to understand and predict changes of complex systems. Here we introduce Turbine, a generic framework enabling fast simulation of any algorithmically definable dynamics on very large... more
Analysis of network dynamics became a focal point to understand and predict changes of complex systems. Here we introduce Turbine, a generic framework enabling fast simulation of any algorithmically definable dynamics on very large networks. Using a perturbation transmission model inspired by communicating vessels, we define a novel centrality measure: perturbation centrality. Hubs and inter-modular nodes proved to be highly efficient in perturbation propagation. High perturbation centrality nodes of the Met-tRNA synthetase protein structure network were identified as amino acids involved in intra-protein communication by earlier studies. Changes in perturbation centralities of yeast interactome nodes upon various stresses well recapitulated the functional changes of stressed yeast cells. The novelty and usefulness of perturbation centrality was validated in several other model, biological and social networks. The Turbine software and the perturbation centrality measure may provide ...
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Cooperation played a significant role in the self-organization and evolution of living organisms. Both network topology and the initial position of cooperators heavily affect the cooperation of social dilemma games. We developed a novel... more
Cooperation played a significant role in the self-organization and evolution of living organisms. Both network topology and the initial position of cooperators heavily affect the cooperation of social dilemma games. We developed a novel simulation program package, called 'NetworGame', which is able to simulate any type of social dilemma games on any model, or real world networks with any assignment of initial cooperation or defection strategies to network nodes. The ability of initially defecting single nodes to break overall cooperation was called as 'game centrality'. The efficiency of this measure was verified on well-known social networks, and was extended to 'protein games', i.e. the simulation of cooperation between proteins, or their amino acids. Hubs and in particular, party hubs of yeast protein-protein interaction networks had a large influence to convert the cooperation of other nodes to defection. Simulations on methionyl-tRNA synthetase protein s...
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During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here, we describe first the protein structure networks of molecular chaperones, then characterize chaperone containing... more
During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here, we describe first the protein structure networks of molecular chaperones, then characterize chaperone containing sub-networks of interactomes called as chaperone-networks or chaperomes. We review the role of molecular chaperones in short-term adaptation of cellular networks in response to stress, and in long-term adaptation discussing their putative functions in the regulation of evolvability. We provide a general overview of possible network mechanisms of adaptation, learning and memory formation. We propose that changes of network rigidity play a key role in learning and memory formation processes. Flexible network topology provides "learning competent" state. Here, networks may have much less modular boundaries than locally rigid, highly modular networks, where the learnt information has already been consolidated in a memory formation process. Since modula...
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Conformational barcodes tag functional sites of proteins, and are decoded by interacting molecules transmitting the incoming signal. Conformational barcodes are modified by all co-occurring allosteric events induced by post-translational... more
Conformational barcodes tag functional sites of proteins, and are decoded by interacting molecules transmitting the incoming signal. Conformational barcodes are modified by all co-occurring allosteric events induced by post-translational modifications, pathogen, drug binding, etc. We argue that fuzziness (plasticity) of conformational barcodes may be increased by disordered protein structures, by integrative plasticity of multi-phosphorylation events, by increased intracellular water content (decreased molecular crowding) and by increased action of molecular chaperones. This leads to increased plasticity of signaling and cellular networks. Increased plasticity is both substantiated by and inducing an increased noise level. Using the versatile network dynamics tool, Turbine (www.turbine.linkgroup.hu), here we show that the 10% noise level expected in cellular systems shifts a cancer-related signaling network of human cells from its proliferative attractors to its largest, apoptotic a...
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Complex systems are successfully reduced to interacting elements via the network concept. Transport plays a key role in the survival of networks. For example the specialized signaling cascades of cellular networks filter noise and... more
Complex systems are successfully reduced to interacting elements via the network concept. Transport plays a key role in the survival of networks. For example the specialized signaling cascades of cellular networks filter noise and efficiently adapt the network structure to new stimuli. However, our general understanding of transport mechanisms and signaling pathways in complex systems is yet limited. Here we summarize the key network structures involved in transport, list the solutions available to overloaded systems for relaxing their load and outline a possible method for the computational determination of signaling pathways. We highlight that in addition to hubs, bridges and the network skeleton, the overlapping modular structure is also essential in network transport. Moreover, by locating network elements in the space of overlapping network modules and evaluating their distance in this "module space", it may be possible to approximate signaling pathways computationall...
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The network approach became a widely used tool to understand the behaviour of complex systems in the last decade. We start from a short description of structural rigidity theory. A detailed account on the combinatorial rigidity analysis... more
The network approach became a widely used tool to understand the behaviour of complex systems in the last decade. We start from a short description of structural rigidity theory. A detailed account on the combinatorial rigidity analysis of protein structures, as well as local flexibility measures of proteins and their applications in explaining allostery and thermostability is given. We also briefly discuss the network aspects of cytoskeletal tensegrity. Finally, we show the importance of the balance between functional flexibility and rigidity in protein-protein interaction, metabolic, gene regulatory and neuronal networks. Our summary raises the possibility that the concepts of flexibility and rigidity can be generalized to all networks.
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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... more
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 and bridges. Extremely long or strong stress may induce a topological phase transition in the respective cellular networks, which switches the cell to a completely different mode of cellular function. We summarize our initial knowledge on network restoration after stress including the role of molecular chaperones in this process. Finally, we discuss the implications of stress-induced network r...
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Recent studies uncovered important core/periphery network structures characterizing complex sets of cooperative and competitive interactions between network nodes, be they proteins, cells, species or humans. Better characterization of the... more
Recent studies uncovered important core/periphery network structures characterizing complex sets of cooperative and competitive interactions between network nodes, be they proteins, cells, species or humans. Better characterization of the structure, dynamics and function of core/periphery networks is a key step of our understanding cellular functions, species adaptation, social and market changes. Here we summarize the current knowledge of the structure and dynamics of "traditional" core/periphery networks, rich-clubs, nested, bow-tie and onion networks. Comparing core/periphery structures with network modules, we discriminate between global and local cores. The core/periphery network organization lies in the middle of several extreme properties, such as random/condensed structures, clique/star configurations, network symmetry/asymmetry, network assortativity/disassortativity, as well as network hierarchy/anti-hierarchy. These properties of high complexity together with th...