Molecular Dynamics–Based Thermodynamic and Kinetic Characterization of Membrane Protein Conformational Transitions

Ogden, Dylan S.; Moradi, Mahmoud

doi:10.1007/978-1-0716-1394-8_16

Cited by 4 publications

(3 citation statements)

References 43 publications

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“…The combination of equilibrium and non-equilibrium MD simulations has proven effective for investigating biological challenges ( Govind Kumar et al, 2022 ; Immadisetty et al, 2021 ; Polasa et al, 2022 ; Moradi et al, 2015 , 2011 , 2014a , b ; Moradi and Tajkhorshid, 2013 ; Ogden and Moradi, 2021 ; Chen et al, 2022 ). In this work, the YidC independent insertion mechanism was studied using non-equilibrium targeted MD (TMD) as implemented within the colvars module of NAMD ( Fiorin et al, 2013 ).…”

Section: Methodsmentioning

confidence: 99%

An investigation of the YidC-mediated membrane insertion of Pf3 coat protein using molecular dynamics simulations

Polasa

Hettige

Immadisetty

et al. 2022

Front. Mol. Biosci.

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YidC is a membrane protein that facilitates the insertion of newly synthesized proteins into lipid membranes. Through YidC, proteins are inserted into the lipid bilayer via the SecYEG-dependent complex. Additionally, YidC functions as a chaperone in protein folding processes. Several studies have provided evidence of its independent insertion mechanism. However, the mechanistic details of the YidC SecY-independent protein insertion mechanism remain elusive at the molecular level. This study elucidates the insertion mechanism of YidC at an atomic level through a combination of equilibrium and non-equilibrium molecular dynamics (MD) simulations. Different docking models of YidC-Pf3 in the lipid bilayer were built in this study to better understand the insertion mechanism. To conduct a complete investigation of the conformational difference between the two docking models developed, we used classical molecular dynamics simulations supplemented with a non-equilibrium technique. Our findings indicate that the YidC transmembrane (TM) groove is essential for this high-affinity interaction and that the hydrophilic nature of the YidC groove plays an important role in protein transport across the cytoplasmic membrane bilayer to the periplasmic side. At different stages of the insertion process, conformational changes in YidC’s TM domain and membrane core have a mechanistic effect on the Pf3 coat protein. Furthermore, during the insertion phase, the hydration and dehydration of the YidC’s hydrophilic groove are critical. These results demonstrate that Pf3 coat protein interactions with the membrane and YidC vary in different conformational states during the insertion process. Finally, this extensive study directly confirms that YidC functions as an independent insertase.

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Section: Methodsmentioning

confidence: 99%

An investigation of the YidC-mediated membrane insertion of Pf3 coat protein using molecular dynamics simulations

Polasa

Hettige

Immadisetty

et al. 2022

Front. Mol. Biosci.

Self Cite

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show abstract

“…The combination of equilibrium and non-equilibrium MD simulations has proven effective for investigating biological challenges. 12,56–64 In this work, the YidC independent insertion mechanism was studied using non-equilibrium targeted MD (TMD) as implemented within the colvars module of NAMD. 65 TMD simulation was performed on the final conformation of the pose 1 system obtained from the 550 ns equilibrium trajectory in order to transfer the Pf3 peptide to the periplasmic side of the membrane, as seen in pose 2.…”

Section: Methodsmentioning

confidence: 99%

An Investigation of the YidC-Mediated Membrane Insertion of Pf3 Coat Protein Using Molecular Dynamics Simulations

Polasa

Hettige

Immadisetty

et al. 2022

Preprint

Self Cite

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YidC is a membrane protein that facilitates the insertion of newly synthesized proteins into lipid membranes. Through YidC, proteins are inserted into the lipid bilayer via the SecYEG-dependent complex. Additionally, YidC functions as a chaperone in protein folding processes. Several studies have provided evidence of its independent insertion mechanism. However, the mechanistic details of the YidC independent protein insertion mechanism remain elusive at the molecular level. This study elucidates the insertion mechanism of YidC at an atomic level through a combination of equilibrium and non-equilibrium molecular dynamics (MD) simulations. Different docking models of YidC-Pf3 in the lipid bilayer were built in this study to better understand the insertion mechanism. To conduct a complete investigation of the conformational difference between the two docking models developed, we used classical molecular dynamics simulations supplemented with a non-equilibrium technique. Our findings indicate that the YidC transmembrane (TM) groove is essential for this high-affinity interaction and that the hydrophilic nature of the YidC groove plays an important role in protein transport across the cytoplasmic membrane bilayer to the periplasmic side. At different stages of the insertion process, conformational changes in YidC’s TM domain and membrane core have a mechanistic effect on the Pf3 coat. Furthermore, during the insertion phase, the hydration and dehydration of the YidC’s hydrophilic groove are critical. These demonstrate that Pf3 interactions with the membrane and YidC vary in different conformational states during the insertion process. Finally, this extensive study directly confirms that YidC functions as an independent insertase.

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“…The final images refined by the String Method were further simulated by performing the umbrella sampling (US) simulation − with distance (between COM H174-D177 and COM I141-A144) as the reaction coordinates. A harmonic biasing potential with a force constant of 12.0 kcal/mol•Å 2 was applied on the distance.…”

Section: Methodsmentioning

confidence: 99%

p38α Kinase Auto-Activation through Its Conformational Transition Induced by Tyr323 Phosphorylation

Zang

Wang

Hao

et al. 2022

J. Chem. Inf. Model.

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p38α is a key serine/threonine kinase that can enable atypical auto-activation through Zap70 phosphorylation and initiate T cell receptor signaling. The auto-activation plays an important role in autoimmune diseases. Although the classical activation mechanism of p38α has been studied in-depth, the atypical activation mechanism of Y323 phosphorylation-induced p38α auto-activation remains largely unexplained, especially the regulatory effects of phosphorylation on different sites (Y323 vs T180). From the X-ray experimental data, we identified the inactive and active states of p38α using principal component analysis. To understand the auto-activation process and the internal driving mechanism, a computational paradigm that couples the targeted molecular dynamics simulations, the String Method, and the umbrella sampling strategy were employed to generate the conformational landscape of p38α, including p38α T180–Y323, p38α T180–pY323, and p38α pT180–pY323 systems (pT180/pY323: phosphorylated T180/Y323). We explored that pY323 could change the conformational distribution and promote the conformational transition of p38α from the inactive state to the active state. Auto-activation of p38α is regulated by pY323 through destabilization of the hydrophobic core structure and aided by R173. This study will further explain the conformational transition of p38α induced by Y323 phosphorylation and provide insights into the universal molecular auto-activation mechanism of the p38 subfamily at the atomic level.

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Molecular Dynamics–Based Thermodynamic and Kinetic Characterization of Membrane Protein Conformational Transitions

Cited by 4 publications

References 43 publications

An investigation of the YidC-mediated membrane insertion of Pf3 coat protein using molecular dynamics simulations

An investigation of the YidC-mediated membrane insertion of Pf3 coat protein using molecular dynamics simulations

An Investigation of the YidC-Mediated Membrane Insertion of Pf3 Coat Protein Using Molecular Dynamics Simulations

p38α Kinase Auto-Activation through Its Conformational Transition Induced by Tyr323 Phosphorylation

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