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Network representation of protein interactions: Theory of graph description and analysis.

ABSTRACT: A methodological framework is presented for the graph theoretical interpretation of NMR data of protein interactions. The proposed analysis generalizes the idea of network representations of protein structures by expanding it to protein interactions. This approach is based on regularization of residue-resolved NMR relaxation times and chemical shift data and subsequent construction of an adjacency matrix that represents the underlying protein interaction as a graph or network. The network nodes represent protein residues. Two nodes are connected if two residues are functionally correlated during the protein interaction event. The analysis of the resulting network enables the quantification of the importance of each amino acid of a protein for its interactions. Furthermore, the determination of the pattern of correlations between residues yields insights into the functional architecture of an interaction. This is of special interest for intrinsically disordered proteins, since the structural (three-dimensional) architecture of these proteins and their complexes is difficult to determine. The power of the proposed methodology is demonstrated at the example of the interaction between the intrinsically disordered protein osteopontin and its natural ligand heparin.

SUBMITTER: Kurzbach D

PROVIDER: S-EPMC5338233 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Network representation of protein interactions: Theory of graph description and analysis.

Kurzbach Dennis D

Protein science : a publication of the Protein Society 20160619 9

A methodological framework is presented for the graph theoretical interpretation of NMR data of protein interactions. The proposed analysis generalizes the idea of network representations of protein structures by expanding it to protein interactions. This approach is based on regularization of residue-resolved NMR relaxation times and chemical shift data and subsequent construction of an adjacency matrix that represents the underlying protein interaction as a graph or network. The network nodes ...[more]

PMID: 27272236

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Project description:BackgroundDevelopment of new methods for analysis of protein-protein interactions (PPIs) at molecular and nanometer scales gives insights into intracellular signaling pathways and will improve understanding of protein functions, as well as other nanoscale structures of biological and abiological origins. Recent advances in computational tools, particularly the ones involving modern deep learning algorithms, have been shown to complement experimental approaches for describing and rationalizing PPIs. However, most of the existing works on PPI predictions use protein-sequence information, and thus have difficulties in accounting for the three-dimensional organization of the protein chains.ResultsIn this study, we address this problem and describe a PPI analysis based on a graph attention network, named Struct2Graph, for identifying PPIs directly from the structural data of folded protein globules. Our method is capable of predicting the PPI with an accuracy of 98.89% on the balanced set consisting of an equal number of positive and negative pairs. On the unbalanced set with the ratio of 1:10 between positive and negative pairs, Struct2Graph achieves a fivefold cross validation average accuracy of 99.42%. Moreover, Struct2Graph can potentially identify residues that likely contribute to the formation of the protein-protein complex. The identification of important residues is tested for two different interaction types: (a) Proteins with multiple ligands competing for the same binding area, (b) Dynamic protein-protein adhesion interaction. Struct2Graph identifies interacting residues with 30% sensitivity, 89% specificity, and 87% accuracy.ConclusionsIn this manuscript, we address the problem of prediction of PPIs using a first of its kind, 3D-structure-based graph attention network (code available at https://github.com/baranwa2/Struct2Graph ). Furthermore, the novel mutual attention mechanism provides insights into likely interaction sites through its unsupervised knowledge selection process. This study demonstrates that a relatively low-dimensional feature embedding learned from graph structures of individual proteins outperforms other modern machine learning classifiers based on global protein features. In addition, through the analysis of single amino acid variations, the attention mechanism shows preference for disease-causing residue variations over benign polymorphisms, demonstrating that it is not limited to interface residues.

Project description:Despite the established effectiveness of the brain-computer interface (BCI) therapy during stroke rehabilitation (Song et al., 2014a, 2015; Young et al., 2014a,b,c, 2015; Remsik et al., 2016), little is understood about the connections between motor network reorganization and functional motor improvements. The aim of this study was to investigate changes in the network reorganization of the motor cortex during BCI therapy. Graph theoretical approaches are used on resting-state functional magnetic resonance imaging (fMRI) data acquired from stroke patients to evaluate these changes. Correlations between changes in graph measurements and behavioral measurements were also examined. Right hemisphere chronic stroke patients (average time from stroke onset = 38.23 months, standard deviation (SD) = 46.27 months, n = 13, 6 males, 10 right-handed) with upper-extremity motor deficits received interventional rehabilitation therapy using a closed-loop neurofeedback BCI device. Eyes-closed resting-state fMRI (rs-fMRI) scans, along with T-1 weighted anatomical scans on 3.0T MRI scanners were collected from these patients at four test points. Immediate therapeutic effects were investigated by comparing pre and post-therapy results. Results displayed that th average clustering coefficient of the motor network increased significantly from pre to post-therapy. Furthermore, increased regional centrality of ipsilesional primary motor area (p = 0.02) and decreases in regional centrality of contralesional thalamus (p = 0.05), basal ganglia (p = 0.05 in betweenness centrality analysis and p = 0.03 for degree centrality), and dentate nucleus (p = 0.03) were observed (uncorrected). These findings suggest an overall trend toward significance in terms of involvement of these regions. Increased centrality of primary motor area may indicate increased efficiency within its interactive network as an effect of BCI therapy. Notably, changes in centrality of the bilateral cerebellum regions have strong correlations with both clinical variables [the Action Research Arm Test (ARAT), and the Nine-Hole Peg Test (9-HPT)].

Project description:BackgroundAlthough a large body of knowledge about both brain structure and function has been gathered over the last decades, we still have a poor understanding of their exact relationship. Graph theory provides a method to study the relation between network structure and function, and its application to neuroscientific data is an emerging research field. We investigated topological changes in large-scale functional brain networks in patients with Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) by means of graph theoretical analysis of resting-state EEG recordings. EEGs of 20 patients with mild to moderate AD, 15 FTLD patients, and 23 non-demented individuals were recorded in an eyes-closed resting-state. The synchronization likelihood (SL), a measure of functional connectivity, was calculated for each sensor pair in 0.5-4 Hz, 4-8 Hz, 8-10 Hz, 10-13 Hz, 13-30 Hz and 30-45 Hz frequency bands. The resulting connectivity matrices were converted to unweighted graphs, whose structure was characterized with several measures: mean clustering coefficient (local connectivity), characteristic path length (global connectivity) and degree correlation (network 'assortativity'). All results were normalized for network size and compared with random control networks.ResultsIn AD, the clustering coefficient decreased in the lower alpha and beta bands (p < 0.001), and the characteristic path length decreased in the lower alpha and gamma bands (p < 0.05) compared to controls. In FTLD no significant differences with controls were found in these measures. The degree correlation decreased in both alpha bands in AD compared to controls (p < 0.05), but increased in the FTLD lower alpha band compared with controls (p < 0.01).ConclusionWith decreasing local and global connectivity parameters, the large-scale functional brain network organization in AD deviates from the optimal 'small-world' network structure towards a more 'random' type. This is associated with less efficient information exchange between brain areas, supporting the disconnection hypothesis of AD. Surprisingly, FTLD patients show changes in the opposite direction, towards a (perhaps excessively) more 'ordered' network structure, possibly reflecting a different underlying pathophysiological process.

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Network representation of protein interactions: Theory of graph description and analysis.

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Network representation of protein interactions: Theory of graph description and analysis.

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