arXiv subjects

Peter Csermely

Publications and source records attributed to Peter Csermely.

44 records · Page 3Linked to original sources

arXiv2007

Stress-induced rearrangements of cellular networks: consequences for protection and drug design

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 rearrangements in diseases and ageing, and propose therapeutic approaches both to increase the robustness and help the repair of cellular networks.

q-bio.MN↗

arXiv2007

Network analysis of protein dynamics

The network paradigm is increasingly used to describe the topology and dynamics of complex systems. Here we review the results of the topological analysis of protein structures as molecular networks describing their small-world character, and the role of hubs and central network elements in governing enzyme activity, allosteric regulation, protein motor function, signal transduction and protein stability. We summarize available data how central network elements are enriched in active centers and ligand binding sites directing the dynamics of the entire protein. We assess the feasibility of conformational and energy networks to simplify the vast complexity of rugged energy landscapes and to predict protein folding and dynamics. Finally, we suggest that modular analysis, novel centrality measures, hierarchical representation of networks and the analysis of network dynamics will soon lead to an expansion of this field.

q-bio.BM↗

arXiv2007

How to design multi-target drugs: Target search options in cellular networks

Despite improved rational drug design and a remarkable progress in genomic, proteomic and high-throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade. Multi-target drugs multiply the number of pharmacologically relevant target molecules by introducing a set of indirect, network-dependent effects. Parallel with this the low-affinity binding of multi-target drugs eases the constraints of druggability, and significantly increases the size of the druggable proteome. These effects tremendously expand the number of potential drug targets, and will introduce novel classes of multi-target drugs with smaller side effects and toxicity. Here we review the recent progress in this field, compare possible network attack strategies, and propose several methods to find target-sets for multi-target drugs.

q-bio.MN↗

arXiv2007

Molecular chaperones: The modular evolution of cellular networks

Molecular chaperones play a prominent role in signaling and transcriptional regulatory networks of the cell. Recent advances uncovered that chaperones act as genetic buffers stabilizing the phenotype of various cells and organisms and may serve as potential regulators of evolvability. Chaperones have weak links, connect hubs, are in the overlaps of network modules and may uncouple these modules during stress, which gives an additional protection for the cell at the network-level. Moreover, after stress chaperones are essential to re-build inter-modular contacts by their low affinity sampling of the potential interaction partners in different modules. This opens the way to the chaperone-regulated modular evolution of cellular networks, and helps us to design novel therapeutic and anti-aging strategies.

q-bio.MN↗

arXiv2006

Aging cellular networks: chaperones as major participants

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 and mitochondrial networks. As aging proceeds, the increased overload of damaged proteins is an especially important element contributing to cellular disintegration and destabilization. Additionally, chaperone overload may contribute to the increase of "noise" in aging cells, which leads to an increased stochastic resonance resulting in a deficient discrimination between signals and noise. Chaperone- and other multi-target therapies, which restore the missing weak links in aging cellular networks, may emerge as important anti-aging interventions.

q-bio.MN↗

arXiv2005

Multiple, weak hits confuse complex systems: A transcriptional regulatory network as an example

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.

q-bio.MN↗

arXiv2005

Water and molecular chaperones act as weak links of protein folding networks: energy landscape and punctuated equilibrium changes point towards a game theory of proteins

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 interactions), which allow the generalization of all these statements to a multitude of networks.

q-bio.BM↗

arXiv2005

The efficiency of multi-target drugs: the network approach might help drug design

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.

q-bio.MN↗