Insight into the Binding of DFG-out Allosteric Inhibitors to B-Raf Kinase Using Molecular Dynamics and Free Energy Calculations

Coronel, Luis; Granadino‐Roldán, José M.; Pinto, Marta; Tomás, M. S.; Pujol, Maria Dolors; Rubio-Martínez, Jaime

doi:10.2174/1573409911666150702100245

Cited by 2 publications

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“…A combination of docking, MD simulations and QM/MM calculations was used to quantify binding and activity of type I BRAF inhibitors [ 73 ]. MD simulations and binding free energy calculations have been employed in computational studies of type II DFG-out inhibitors in complexes with the BRAF-V600E mutant [ 75 ]. Enhanced MD simulations have suggested a mechanism in which oncogenic BRAF mutations could kinetically trap the kinase in the active form by increasing the barriers of conformational transitions between the inactive and active kinase states [ 76 ].…”

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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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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A Multistep Docking and Scoring Protocol for Congeneric Series: Implementation on Kinase DFG-Out Type II Inhibitors

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Insight into the Binding of DFG-out Allosteric Inhibitors to B-Raf Kinase Using Molecular Dynamics and Free Energy Calculations

Abstract: role. This work also provides a better structural understanding of the binding of DFG-out inhibitors to V600E BRaf, which can be used in a further step for rational design of a new class of B-Raf potent inhibitors.

Cited by 2 publications

References 45 publications

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

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

A Multistep Docking and Scoring Protocol for Congeneric Series: Implementation on Kinase DFG-Out Type II Inhibitors

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