Molecular Evolution of Protein Conformational Changes Revealed by a Network of Evolutionarily Coupled Residues

Jeon, Jouhyun; Nam, Hyun‐Jun; Choi, Yoon Sup; Yang, Jae-Seong; Hwang, Jihye; Kim, Sanguk

doi:10.1093/molbev/msr094

Cited by 44 publications

(37 citation statements)

References 78 publications

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“…While high pMI sites in the Hsp70 structures corresponded mostly to structurally stable residues, coevolving positions exhibited a wide range of conformational mobility with the peaks pointing to the middle part of the spectrum. These findings corroborated with evolutionary studies of protein dynamics [110,111] suggesting that highly coevolving residues may preferentially occupy regions of intermediate mobility. We argue that conformational variability of highly coevolving residues that surround rigid regulatory sites may enable concerted rearrangements of specific interactions associated with global allosteric changes.…”

Section: Resultssupporting

confidence: 86%

“…However, the vast majority of residues with high cMI scores tend to occupy flexible regions, primarily in the subdomain II of the NBD and the substrate binding region ( Fig 5C and 5D ). These observations corroborated with the notion that coevolving flexible residues undergoing cooperative structural changes may constitute recognition elements of substrate binding sites [110,111] . Another group of regulatory Hsp70 residues (D326, K414, N415, Q442 and D481) revealed high cMI scores and intermediate mobility level ( Figs 4 and 5 ).…”

Section: Resultssupporting

confidence: 80%

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Computational Analysis of Residue Interaction Networks and Coevolutionary Relationships in the Hsp70 Chaperones: A Community-Hopping Model of Allosteric Regulation and Communication

2017

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Allosteric interactions in the Hsp70 proteins are linked with their regulatory mechanisms and cellular functions. Despite significant progress in structural and functional characterization of the Hsp70 proteins fundamental questions concerning modularity of the allosteric interaction networks and hierarchy of signaling pathways in the Hsp70 chaperones remained largely unexplored and poorly understood. In this work, we proposed an integrated computational strategy that combined atomistic and coarse-grained simulations with coevolutionary analysis and network modeling of the residue interactions. A novel aspect of this work is the incorporation of dynamic residue correlations and coevolutionary residue dependencies in the construction of allosteric interaction networks and signaling pathways. We found that functional sites involved in allosteric regulation of Hsp70 may be characterized by structural stability, proximity to global hinge centers and local structural environment that is enriched by highly coevolving flexible residues. These specific characteristics may be necessary for regulation of allosteric structural transitions and could distinguish regulatory sites from nonfunctional conserved residues. The observed confluence of dynamics correlations and coevolutionary residue couplings with global networking features may determine modular organization of allosteric interactions and dictate localization of key mediating sites. Community analysis of the residue interaction networks revealed that concerted rearrangements of local interacting modules at the inter-domain interface may be responsible for global structural changes and a population shift in the DnaK chaperone. The inter-domain communities in the Hsp70 structures harbor the majority of regulatory residues involved in allosteric signaling, suggesting that these sites could be integral to the network organization and coordination of structural changes. Using a network-based formalism of allostery, we introduced a community-hopping model of allosteric communication. Atomistic reconstruction of signaling pathways in the DnaK structures captured a direction-specific mechanism and molecular details of signal transmission that are fully consistent with the mutagenesis experiments. The results of our study reconciled structural and functional experiments from a network-centric perspective by showing that global properties of the residue interaction networks and coevolutionary signatures may be linked with specificity and diversity of allosteric regulation mechanisms.

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Section: Resultssupporting

confidence: 86%

Section: Resultssupporting

confidence: 80%

Computational Analysis of Residue Interaction Networks and Coevolutionary Relationships in the Hsp70 Chaperones: A Community-Hopping Model of Allosteric Regulation and Communication

2017

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“…These findings suggested that coevolutionary networks may form direct pathways for transmitting allosteric signals [ 100 ]. The most probable path in the Dabrafenib-BRAF complex (85% occupancy) could proceed from F595 of monomer A to the R-spine residues of the αC-helix (V504, L505), subsequently reaching to the interfacial residue R509 of the monomer A ( Fig 12B ).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, coevolving residues are often located close to each other in the protein structure [ 96,97 ] and may form independent structural modules (or protein sectors) with distinct biochemical functions [ 88–90,98,99 ]. Functional conformational changes could be often enabled through networks of evolutionarily coupled residues [ 100 ].…”

Section: Introductionmentioning

confidence: 99%

Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways

Tse

Verkhivker

2016

PLoS ONE

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The recent studies have revealed that most BRAF inhibitors can paradoxically induce kinase activation by promoting dimerization and enzyme transactivation. Despite rapidly growing number of structural and functional studies about the BRAF dimer complexes, the molecular basis of paradoxical activation phenomenon is poorly understood and remains largely hypothetical. In this work, we have explored the relationships between inhibitor binding, protein dynamics and allosteric signaling in the BRAF dimers using a network-centric approach. Using this theoretical framework, we have combined molecular dynamics simulations with coevolutionary analysis and modeling of the residue interaction networks to determine molecular determinants of paradoxical activation. We have investigated functional effects produced by paradox inducer inhibitors PLX4720, Dabrafenib, Vemurafenib and a paradox breaker inhibitor PLX7904. Functional dynamics and binding free energy analyses of the BRAF dimer complexes have suggested that negative cooperativity effect and dimer-promoting potential of the inhibitors could be important drivers of paradoxical activation. We have introduced a protein structure network model in which coevolutionary residue dependencies and dynamic maps of residue correlations are integrated in the construction and analysis of the residue interaction networks. The results have shown that coevolutionary residues in the BRAF structures could assemble into independent structural modules and form a global interaction network that may promote dimerization. We have also found that BRAF inhibitors could modulate centrality and communication propensities of global mediating centers in the residue interaction networks. By simulating allosteric communication pathways in the BRAF structures, we have determined that paradox inducer and breaker inhibitors may activate specific signaling routes that correlate with the extent of paradoxical activation. While paradox inducer inhibitors may facilitate a rapid and efficient communication via an optimal single pathway, the paradox breaker may induce a broader ensemble of suboptimal and less efficient communication routes. The central finding of our study is that paradox breaker PLX7904 could mimic structural, dynamic and network features of the inactive BRAF-WT monomer that may be required for evading paradoxical activation. The results of this study rationalize the existing structure-functional experiments by offering a network-centric rationale of the paradoxical activation phenomenon. We argue that BRAF inhibitors that amplify dynamic features of the inactive BRAF-WT monomer and intervene with the allosteric interaction networks may serve as effective paradox breakers in cellular environment.

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“…• Combination of evolutionary conservation data has proven to be an efficient predictor of intra-protein signaling pathways [60,85,[210][211][212]. Similar approaches may be extended to protein neighborhoods helping to find starting sites for allo-network drug action.…”

Section: Possible Methods To Identify Allo-network Drug Targetsmentioning

confidence: 99%

Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

Szilágyi¹,

Nussinov²,

Csermely

2013

CTMC

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Allosteric drugs are usually more specific and have fewer side effects than orthosteric drugs targeting the same protein. Here, we overview the current knowledge on allosteric signal transmission from the network point of view, and show that most intra-protein conformational changes may be dynamically transmitted across protein-protein interaction and signaling networks of the cell. Allo-network drugs influence the pharmacological target protein indirectly using specific inter-protein network pathways. We show that allo-network drugs may have a higher efficiency to change the networks of human cells than those of other organisms, and can be designed to have specific effects on cells in a diseased state. Finally, we summarize possible methods to identify allo-network drug targets and sites, which may develop to a promising new area of systems-based drug design.

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Molecular Evolution of Protein Conformational Changes Revealed by a Network of Evolutionarily Coupled Residues

Cited by 44 publications

References 78 publications

Computational Analysis of Residue Interaction Networks and Coevolutionary Relationships in the Hsp70 Chaperones: A Community-Hopping Model of Allosteric Regulation and Communication

Computational Analysis of Residue Interaction Networks and Coevolutionary Relationships in the Hsp70 Chaperones: A Community-Hopping Model of Allosteric Regulation and Communication

Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways

Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

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