Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps

Mársico, Franco; Burastero, Osvaldo; Defelipe, Lucas A.; Lopez, Elias Daniel; Arrar, Mehrnoosh; Turjanski, Adrián; Martí, Marcelo A.

doi:10.1016/j.bbrc.2017.09.039

Cited by 11 publications

(14 citation statements)

References 39 publications

(35 reference statements)

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“…Concerning D189 HK , it can be predicted that this highly conserved acidic residue at position H+1 (one residue C-terminal to the phosphorylatable His), is not involved in the phosphoryl-transfer reaction. This is in contrast with the critical role that this residue plays in subtracting a proton from the His δN, increasing the nucleophilicity of the His in the autophosphorylation reaction 10,13,34,35 . In the phosphotransferase state, due to the rotameric configuration of H188 HK , the δN is oriented in a way that cannot interact with D189 HK .…”

Section: Highly Conserved D189 Hk and T80 Rr Residues Are Not Essential For Phosphoryltransfermentioning

confidence: 80%

“…To study both the phosphotransfer and the phosphatase reaction mechanisms, we used a multiple steered molecular dynamics (MSMD) strategy, combined with Jarzynski's relationship to determine the corresponding Free Energy Profiles. This strategy has already been shown to be useful in previous works from our group for phosphoryl transfer reactions 35,53,54 . Briefly, in MSMD the system is driven "multiple" times along the selected reaction coordinate under nonequilibrium conditions, by applying an external force, and for each individual trajectory, the work performed by the external force is computed.…”

Section: Multiple Steered Molecular Dynamics Protocolmentioning

confidence: 90%

“…The copyright holder for this preprint this version posted November 12, 2021. ; https://doi.org/10.1101/2021.11.12.468217 doi: bioRxiv preprint strategy has already been shown to be useful in previous works from our group for phosphoryl transfer reactions 35,53,54 . Briefly, in MSMD the system is driven "multiple" times along the selected reaction coordinate under nonequilibrium conditions, by applying an external force, and for each individual trajectory, the work performed by the external force is computed.…”

Section: Multiple Steered Molecular Dynamics Protocolmentioning

confidence: 99%

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Molecular basis of unidirectional information transmission in two-component systems: lessons from the DesK-DesR thermosensor

Lima

Blanco

Olivieri

et al. 2021

Preprint

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Cellular signaling systems transmit information over long distances using allosteric transitions and/or post-translational modifications. In two-component systems the sensor histidine kinase and response regulator are wired through phosphoryl-transfer reactions, using either a uni- or bi-directional transmission mode, allowing to build rich regulatory networks. Using the thermosensor DesK-DesR two-component system from Bacillus subtilis and combining crystal structures, QM/MM calculations and integrative kinetic modeling, we uncover that: i) longer or shorter distances between the phosphoryl-acceptor and -donor residues can shift the phosphoryl-transfer equilibrium; ii) the phosphorylation-dependent dimerization of the regulator acts as a sequestering mechanism by preventing the interaction with the histidine kinase; and iii) the kinase's intrinsic conformational equilibrium makes the phosphotransferase state unlikely in the absence of histidine phosphorylation, minimizing backwards transmission. These mechanisms allow the system to control the direction of signal transmission in a very efficient way, showcasing the key role that structure-encoded allostery plays in signaling proteins to store and transmit information.

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Section: Highly Conserved D189 Hk and T80 Rr Residues Are Not Essential For Phosphoryltransfermentioning

confidence: 80%

Section: Multiple Steered Molecular Dynamics Protocolmentioning

confidence: 90%

Section: Multiple Steered Molecular Dynamics Protocolmentioning

confidence: 99%

See 1 more Smart Citation

Molecular basis of unidirectional information transmission in two-component systems: lessons from the DesK-DesR thermosensor

Lima

Blanco

Olivieri

et al. 2021

Preprint

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“…In previous work from our group, 19 we used multiscale modeling techniques (coarse grain, MD and QM/MM) to study both HK conformational and chemical steps in CpxA, a trans-acting HK which senses envelope stress response by activating expression of downstream genes. Our previous results showed two important aspects that suggested there is tight coupling between CpxA conformational and chemical steps.…”

Section: ■ Introductionmentioning

confidence: 99%

Conformational and Reaction Dynamic Coupling in Histidine Kinases: Insights from Hybrid QM/MM Simulations

Olivieri

Burastero

Drusin

et al. 2020

J. Chem. Inf. Model.

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Histidine kinases (HK) of bacterial two-component systems represent a hallmark of allosterism in proteins, being able to detect a signal through the sensor domain and transmit this information through the protein matrix to the kinase domain which, once active, autophosphorylates a specific histidine residue. Inactive-to-active transition results in a large conformational change that moves the kinase on top of the histidine. In the present work, we use several molecular simulation techniques (Molecular Dynamics, Hybrid QM/MM, and constant pH molecular dynamics) to study the activation and autophosphorylation reactions in L. plantarum WalK, a cis-acting HK. In agreement with previous results, we show that the chemical step requires tight coupling with the conformational step in order to maintain the histidine phosphoacceptor in the correct tautomeric state, with a reactive δ-nitrogen. During the conformational transition, the kinase domain is never released and walks along the HK helix axis, breaking and forming several conserved residue-based contacts. The phosphate transfer reaction is concerted in the transition state region and is catalyzed through the stabilization of the negative developing charge of transferring phosphate along the reaction.

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“…The change in free energy governs all chemical processes. The calculation of free energy profiles, that is, the change in free energy along a transformation or reaction coordinate, has thus been critical in understanding many complex processes such as protein–protein recognition (Gohlke, Kiel, & Case, ; Isralewitz, Baudry, Gullingsrud, Kosztin, & Schulten, 2001), drug design (Isralewitz et al., 2001; Shirts, Mobley, & Brown, ), ligand binding kinetics (Boechi et al., ; Boubeta, Bari, Estrin, & Boechi, ; Hu, Xu, & Wang, ; Selvam, Wereszczynski, & Tikhonova, ; Xiong, Crespo, Marti, Estrin, & Roitberg, ), large‐scale conformational reorganization in proteins (Bringas, Petruk, Estrin, Capece, & Martí, ; Isralewitz, Gao, & Schulten, 2001; Marsico et al., ), and in the elucidation of chemical reaction mechanisms in enzyme active sites (Bieza et al., ; Crespo, Martí, Estrin, & Roitberg, ).…”

Section: Introductionmentioning

confidence: 99%

Lessons learned about steered molecular dynamics simulations and free energy calculations

et al. 2019

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The calculation of free energy profiles is central in understanding differential enzymatic activity, for instance, involving chemical reactions that require QM‐MM tools, ligand migration, and conformational rearrangements that can be modeled using classical potentials. The use of steered molecular dynamics (sMD) together with the Jarzynski equality is a popular approach in calculating free energy profiles. Here, we first briefly review the application of the Jarzynski equality to sMD simulations, then revisit the so‐called stiff‐spring approximation and the consequent expectation of Gaussian work distributions and, finally, reiterate the practical utility of the second‐order cumulant expansion, as it coincides with the parametric maximum‐likelihood estimator in this scenario. We illustrate this procedure using simulations of CO, both in aqueous solution and in a carbon nanotube as a model system for biologically relevant nanoheterogeneous environments. We conclude the use of the second‐order cumulant expansion permits the use of faster pulling velocities in sMD simulations, without introducing bias due to large dispersion in the non‐equilibrium work distribution.

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Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps

Cited by 11 publications

References 39 publications

Molecular basis of unidirectional information transmission in two-component systems: lessons from the DesK-DesR thermosensor

Molecular basis of unidirectional information transmission in two-component systems: lessons from the DesK-DesR thermosensor

Conformational and Reaction Dynamic Coupling in Histidine Kinases: Insights from Hybrid QM/MM Simulations

Lessons learned about steered molecular dynamics simulations and free energy calculations

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