An automated approach to network features of protein structure ensembles

Bhattacharyya, Moitrayee; Bhat, Chanda R; Vishveshwara, Saraswathi

doi:10.1002/pro.2333

Cited by 58 publications

(63 citation statements)

References 53 publications

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“…The details of the construction of such a network at a particular interaction cut-off (Imin) and its implications have been previously described 18,50,51 . Typically, an I min value between 2 – 3% is chosen to compute the interaction networks as discussed earlier 19,20,52 . Here, the construction of protein structure network and subsequent analysis is carried out using the PSN-Ensemble software 19 .…”

Section: Star Methodsmentioning

confidence: 99%

“…Typically, an I min value between 2 – 3% is chosen to compute the interaction networks as discussed earlier 19,20,52 . Here, the construction of protein structure network and subsequent analysis is carried out using the PSN-Ensemble software 19 . The high-resolution crystal structures of Fus3 in the apo state (PDB_id: 8732B9F, 1.8 Å) or in the Ste5 (PBD_id: 2F49; 1.9 Å) o r Ste7 (PBD_id: 2B9H; 1.55 Å) bound state were used to construct the corresponding protein structure networks for analysis.…”

Section: Star Methodsmentioning

confidence: 99%

“…The residues which appear in more than 10% of these SPs are termed as junction nodes and are considered to be key mediators of allosteric communication between these domains in the protein 19,51 .…”

Section: Star Methodsmentioning

confidence: 99%

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Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity

et al. 2018

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The functional diversity of kinases enables specificity in cellular signal transduction. Yet how more than 500 members of the human kinome specifically receive regulatory inputs and convey information to appropriate substrates-all while using the common signaling output of phosphorylation-remains enigmatic. Here, we perform statistical co-evolution analysis, mutational scanning, and quantitative live-cell assays to reveal a hierarchical organization of the kinase domain that facilitates the orthogonal evolution of regulatory inputs and substrate outputs while maintaining catalytic function. We find that three quasi-independent "sectors"-groups of evolutionarily coupled residues-represent functional units in the kinase domain that encode for catalytic activity, substrate specificity, and regulation. Sector positions impact both disease and pharmacology: the catalytic sector is significantly enriched for somatic cancer mutations, and residues in the regulatory sector interact with allosteric kinase inhibitors. We propose that this functional architecture endows the kinase domain with inherent regulatory plasticity.

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Section: Star Methodsmentioning

confidence: 99%

Section: Star Methodsmentioning

confidence: 99%

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Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity

et al. 2018

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“…A number of complex network approaches have been utilized to identify key residues for different purposes in a network of interacting protein residues. These approaches typically employ some notion of network centrality either by node degree, number of paths (betweenness), graph distance (closeness) or some combination of these [26][27][28]. We tried several of these strategies and found closeness based on estimated path commute time performed the best.…”

Section: Fig 5 Leftmentioning

confidence: 99%

Comparing local search paths with global search paths on protein residue networks: allosteric communication

Khor

2016

jcomplexnetw

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Although proteins have been recognized as small-world networks and their small-world network properties of clustering and short paths have been exploited computationally to produce biologically relevant information, they have not been truly explored as such, i.e. as navigable small-world networks in the original spirit of Milgram's work. This research seeks to fill this gap by exploring local search on a network representation of proteins and to probe the source of navigability in proteins. Previously, we confirmed that proteins are navigable small-world networks and observed that local search paths exhibit different characteristics from global search paths. In this paper, we investigate the biological relevance of the differences in path characteristics on a type III receptor tyrosine kinase (KIT). A chief difference that works in favour of local search paths as intra-protein communication pathways is their weaker proclivity, compared to global search paths, for traversing long-range edges. Long-range edges tend to be less stable and their inclusion tends to decrease the communication propensity of a path. The source of protein navigability is traced to clustering provided by short-range edges. The majority of a protein's short-range edges reside within structures deemed important for long-range energy transport and modulation of allosteric communication in proteins. Therefore, the disruption of intra-protein communication as a result of the destruction of these structures via random rewiring is expected. A local search perspective leads us to this expected conclusion while a global search perspective does not. These findings initiate the compilation of a list of path properties that are characteristic of intra-protein pathways and could suggest fresh avenues for evolving and regulating navigable (small-world) networks.

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“…To understand how protein function changes upon external perturbation, such as protein-protein/ligand binding, mutation, or voltage change, numerous researchers have implemented variants of allosteric network concepts to biomolecules [1][2][3][4][5][6][7][8][9][10][11][12] . One important application of network theory in the context of structural dynamics of biomolecules is to determine which amino acid residues in a protein play an essential role in the propagation of signals within a protein or between proteins by constructing a network of interactions between amino acid residues.…”

Section: Introductionmentioning

confidence: 99%

Robust Determination of Protein Allosteric Signaling Pathways

Botello‐Smith

Luo

2019

Preprint

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To understand how protein function changes upon an allosteric perturbation, such as ligand binding and mutation, significant progress in characterizing allosteric network from molecular dynamics (MD) simulations has been made. However, determining which amino acid(s) play an essential role in the propagation of signals may prove challenging, even when the location of the source and sink is known for a protein or protein complex. This challenge is mainly due to the large fluctuations in protein dynamics that cause instability of the network topology within a single trajectory or between multiple replicas. To solve this problem, we introduce the current-flow betweenness scheme, originated from electrical network theory, to protein dynamical network analysis. To demonstrate the benefit of this new method, we chose a prototypic allosteric enzyme (IGPS or HisH-HisF dimer) as our benchmark system. Using multiple replicas of simulations and multiple network topology comparison metrics (edge ranking, path length, and node frequency), we show that the current-flow betweenness provides a significant improvement in the convergence of the allosteric networks. The improved stability of the network topology allows us to generate a delta-network between the apo and holo forms of the protein. We illustrated that the deltanetwork is a more rigorous way to capture the subtle changes in the networks that would otherwise be neglected by comparing node usage frequencies alone. We have also investigated the use of a linear smoothing function to improve the stability of the contact map. The methodology presented here is general and may be applied to other topology and weighting schemes. We thus conclude that, for determining protein signaling pathways between the pair(s) of source and sink, multiple MD simulation replicas are necessary and the current-flow betweenness scheme introduced here provides a more robust approach than the geodesic scheme based on correlation edge weighting.

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An automated approach to network features of protein structure ensembles

Cited by 58 publications

References 53 publications

Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity

Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity

Comparing local search paths with global search paths on protein residue networks: allosteric communication

Robust Determination of Protein Allosteric Signaling Pathways

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