10,310 research outputs found
Systems approaches and algorithms for discovery of combinatorial therapies
Effective therapy of complex diseases requires control of highly non-linear
complex networks that remain incompletely characterized. In particular, drug
intervention can be seen as control of signaling in cellular networks.
Identification of control parameters presents an extreme challenge due to the
combinatorial explosion of control possibilities in combination therapy and to
the incomplete knowledge of the systems biology of cells. In this review paper
we describe the main current and proposed approaches to the design of
combinatorial therapies, including the empirical methods used now by clinicians
and alternative approaches suggested recently by several authors. New
approaches for designing combinations arising from systems biology are
described. We discuss in special detail the design of algorithms that identify
optimal control parameters in cellular networks based on a quantitative
characterization of control landscapes, maximizing utilization of incomplete
knowledge of the state and structure of intracellular networks. The use of new
technology for high-throughput measurements is key to these new approaches to
combination therapy and essential for the characterization of control
landscapes and implementation of the algorithms. Combinatorial optimization in
medical therapy is also compared with the combinatorial optimization of
engineering and materials science and similarities and differences are
delineated.Comment: 25 page
GraphCombEx: A Software Tool for Exploration of Combinatorial Optimisation Properties of Large Graphs
We present a prototype of a software tool for exploration of multiple
combinatorial optimisation problems in large real-world and synthetic complex
networks. Our tool, called GraphCombEx (an acronym of Graph Combinatorial
Explorer), provides a unified framework for scalable computation and
presentation of high-quality suboptimal solutions and bounds for a number of
widely studied combinatorial optimisation problems. Efficient representation
and applicability to large-scale graphs and complex networks are particularly
considered in its design. The problems currently supported include maximum
clique, graph colouring, maximum independent set, minimum vertex clique
covering, minimum dominating set, as well as the longest simple cycle problem.
Suboptimal solutions and intervals for optimal objective values are estimated
using scalable heuristics. The tool is designed with extensibility in mind,
with the view of further problems and both new fast and high-performance
heuristics to be added in the future. GraphCombEx has already been successfully
used as a support tool in a number of recent research studies using
combinatorial optimisation to analyse complex networks, indicating its promise
as a research software tool
A generative model for protein contact networks
In this paper we present a generative model for protein contact networks. The
soundness of the proposed model is investigated by focusing primarily on
mesoscopic properties elaborated from the spectra of the graph Laplacian. To
complement the analysis, we study also classical topological descriptors, such
as statistics of the shortest paths and the important feature of modularity.
Our experiments show that the proposed model results in a considerable
improvement with respect to two suitably chosen generative mechanisms,
mimicking with better approximation real protein contact networks in terms of
diffusion properties elaborated from the Laplacian spectra. However, as well as
the other considered models, it does not reproduce with sufficient accuracy the
shortest paths structure. To compensate this drawback, we designed a second
step involving a targeted edge reconfiguration process. The ensemble of
reconfigured networks denotes improvements that are statistically significant.
As a byproduct of our study, we demonstrate that modularity, a well-known
property of proteins, does not entirely explain the actual network architecture
characterizing protein contact networks. In fact, we conclude that modularity,
intended as a quantification of an underlying community structure, should be
considered as an emergent property of the structural organization of proteins.
Interestingly, such a property is suitably optimized in protein contact
networks together with the feature of path efficiency.Comment: 18 pages, 67 reference
Tradeoff Between Stability and Multispecificity in the Design of Promiscuous Proteins
Natural proteins often partake in several highly specific protein-protein interactions. They are thus subject to multiple opposing forces during evolutionary selection. To be functional, such multispecific proteins need to be stable in complex with each interaction partner, and, at the same time, to maintain affinity toward all partners. How is this multispecificity acquired through natural evolution? To answer this compelling question, we study a prototypical multispecific protein, calmodulin (CaM), which has evolved to interact with hundreds of target proteins. Starting from high-resolution structures of sixteen CaM-target complexes, we employ state-of-the-art computational methods to predict a hundred CaM sequences best suited for interaction with each individual CaM target. Then, we design CaM sequences most compatible with each possible combination of two, three, and all sixteen targets simultaneously, producing almost 70,000 low energy CaM sequences. By comparing these sequences and their energies, we gain insight into how nature has managed to find the compromise between the need for favorable interaction energies and the need for multispecificity. We observe that designing for more partners simultaneously yields CaM sequences that better match natural sequence profiles, thus emphasizing the importance of such strategies in nature. Furthermore, we show that the CaM binding interface can be nicely partitioned into positions that are critical for the affinity of all CaM-target complexes and those that are molded to provide interaction specificity. We reveal several basic categories of sequence-level tradeoffs that enable the compromise necessary for the promiscuity of this protein. We also thoroughly quantify the tradeoff between interaction energetics and multispecificity and find that facilitating seemingly competing interactions requires only a small deviation from optimal energies. We conclude that multispecific proteins have been subjected to a rigorous optimization process that has fine-tuned their sequences for interactions with a precise set of targets, thus conferring their multiple cellular functions
Computational Prediction of Heme-Binding Residues by Exploiting Residue Interaction Network
Computational identification of heme-binding residues is beneficial for predicting and designing novel heme proteins. Here we proposed a novel method for heme-binding residue prediction by exploiting topological properties of these residues in the residue interaction networks derived from three-dimensional structures. Comprehensive analysis showed that key residues located in heme-binding regions are generally associated with the nodes with higher degree, closeness and betweenness, but lower clustering coefficient in the network. HemeNet, a support vector machine (SVM) based predictor, was developed to identify heme-binding residues by combining topological features with existing sequence and structural features. The results showed that incorporation of network-based features significantly improved the prediction performance. We also compared the residue interaction networks of heme proteins before and after heme binding and found that the topological features can well characterize the heme-binding sites of apo structures as well as those of holo structures, which led to reliable performance improvement as we applied HemeNet to predicting the binding residues of proteins in the heme-free state. HemeNet web server is freely accessible at http://mleg.cse.sc.edu/hemeNet/
InteractoMIX:A suite of computational tools to exploit interactomes in biological and clinical research
Virtually all the biological processes that occur inside or outside cells are mediated by protein–protein interactions (PPIs). Hence, the charting and description of the PPI network, initially in organisms, the interactome, but more recently in specific tissues, is essential to fully understand cellular processes both in health and disease. The study of PPIs is also at the heart of renewed efforts in the medical and biotechnological arena in the quest of new therapeutic targets and drugs. Here, we present a mini review of 11 computational tools and resources tools developed by us to address different aspects of PPIs: from interactome level to their atomic 3D structural details. We provided details on each specific resource, aims and purpose and compare with equivalent tools in the literature. All the tools are presented in a centralized, one-stop, web site: InteractoMIX (http://interactomix.com)
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