scholarly journals Insights into structure and dynamics of extracellular domain of Toll-like receptor 5 in Cirrhinus mrigala (mrigala): A molecular dynamics simulation approach

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245358
Author(s):  
Ajaya Kumar Rout ◽  
Varsha Acharya ◽  
Diptimayee Maharana ◽  
Budheswar Dehury ◽  
Sheela Rani Udgata ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Extracellular Domain ◽  
Receptor Activation ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Lateral Side ◽  
Toll Like Receptor ◽  
Cirrhinus Mrigala ◽  
Free Energy Decomposition ◽  
Toll Like Receptor 5

The toll-like receptor 5 (TLR5) is the most conserved important pattern recognition receptors (PRRs) often stimulated by bacterial flagellins and plays a major role in the first-line defense against invading pathogenic bacteria and in immune homeostasis. Experimental crystallographic studies have shown that the extracellular domain (ECD) of TLR5 recognizes flagellin of bacteria and functions as a homodimer in model organism zebrafish. However, no structural information is available on TLR5 functionality in the major carp Cirrhinus mrigala (mrigala) and its interaction with bacterial flagellins. Therefore, the present study was undertaken to unravel the structural basis of TLR5-flagellin recognition in mrigala using structural homodimeric TLR5-flagellin complex of zebrafish as reference. Integrative structural modeling and molecular dynamics simulations were employed to explore the structural and mechanistic details of TLR5 recognition. Results from structural snapshots of MD simulation revealed that TLR5 consistently formed close interactions with the three helices of the D1 domain in flagellin on its lateral side mediated by several conserved amino acids. Results from the intermolecular contact analysis perfectly substantiate with the findings of per residue-free energy decomposition analysis. The differential recognition mediated by flagellin to TLR5 in mrigala involves charged residues at the interface of binding as compared to the zebrafish complex. Overall our results shows TLR5 of mrigala involved in innate immunity specifically recognized a conserved site on flagellin which advocates the scientific community to explore host-specific differences in receptor activation.

scholarly journals Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein–Peptide Docking and Molecular Dynamics Simulation

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 3018 ◽  
Author(s):  
Gao Tu ◽  
Tingting Fu ◽  
Fengyuan Yang ◽  
Lixia Yao ◽  
Weiwei Xue ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Electrostatic Interactions ◽  
Binding Free Energy ◽  
Computational Simulation ◽  
Critical Role ◽  
Dynamics Simulation ◽  
Peptide Docking ◽  
C Terminus ◽  
Free Energy Decomposition

The interaction of death-associated protein kinase 1 (DAPK1) with the 2B subunit (GluN2B) C-terminus of N-methyl-D-aspartate receptor (NMDAR) plays a critical role in the pathophysiology of depression and is considered a potential target for the structure-based discovery of new antidepressants. However, the 3D structures of C-terminus residues 1290–1310 of GluN2B (GluN2B-CT1290-1310) remain elusive and the interaction between GluN2B-CT1290-1310 and DAPK1 is unknown. In this study, the mechanism of interaction between DAPK1 and GluN2B-CT1290-1310 was predicted by computational simulation methods including protein–peptide docking and molecular dynamics (MD) simulation. Based on the equilibrated MD trajectory, the total binding free energy between GluN2B-CT1290-1310 and DAPK1 was computed by the mechanics generalized born surface area (MM/GBSA) approach. The simulation results showed that hydrophobic, van der Waals, and electrostatic interactions are responsible for the binding of GluN2B-CT1290–1310/DAPK1. Moreover, through per-residue free energy decomposition and in silico alanine scanning analysis, hotspot residues between GluN2B-CT1290-1310 and DAPK1 interface were identified. In conclusion, this work predicted the binding mode and quantitatively characterized the protein–peptide interface, which will aid in the discovery of novel drugs targeting the GluN2B-CT1290-1310 and DAPK1 interface.

scholarly journals The Dynamics of the Neuropeptide Y Receptor Type 1 Investigated by Solid-State NMR and Molecular Dynamics Simulation

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5489
Author(s):  
Alexander Vogel ◽  
Mathias Bosse ◽  
Marcel Gauglitz ◽  
Sarah Wistuba ◽  
Peter Schmidt ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Solid State ◽  
Neuropeptide Y ◽  
Solid State Nmr ◽  
Bound State ◽  
Receptor Activation ◽  
Order Parameters ◽  
Dynamics Simulation ◽  
15N Nmr

We report data on the structural dynamics of the neuropeptide Y (NPY) G-protein-coupled receptor (GPCR) type 1 (Y1R), a typical representative of class A peptide ligand GPCRs, using a combination of solid-state NMR and molecular dynamics (MD) simulation. First, the equilibrium dynamics of Y1R were studied using 15N-NMR and quantitative determination of 1H-13C order parameters through the measurement of dipolar couplings in separated-local-field NMR experiments. Order parameters reporting the amplitudes of the molecular motions of the C-H bond vectors of Y1R in DMPC membranes are 0.57 for the Cα sites and lower in the side chains (0.37 for the CH2 and 0.18 for the CH3 groups). Different NMR excitation schemes identify relatively rigid and also dynamic segments of the molecule. In monounsaturated membranes composed of longer lipid chains, Y1R is more rigid, attributed to a higher hydrophobic thickness of the lipid membrane. The presence of an antagonist or NPY has little influence on the amplitude of motions, whereas the addition of agonist and arrestin led to a pronounced rigidization. To investigate Y1R dynamics with site resolution, we conducted extensive all-atom MD simulations of the apo and antagonist-bound state. In each state, three replicas with a length of 20 μs (with one exception, where the trajectory length was 10 μs) were conducted. In these simulations, order parameters of each residue were determined and showed high values in the transmembrane helices, whereas the loops and termini exhibit much lower order. The extracellular helix segments undergo larger amplitude motions than their intracellular counterparts, whereas the opposite is observed for the loops, Helix 8, and termini. Only minor differences in order were observed between the apo and antagonist-bound state, whereas the time scale of the motions is shorter for the apo state. Although these relatively fast motions occurring with correlation times of ns up to a few µs have no direct relevance for receptor activation, it is believed that they represent the prerequisite for larger conformational transitions in proteins.

Ab InitioModeling and Molecular Dynamics Simulation of the α1b-Adrenergic Receptor Activation

Methods ◽  
1998 ◽  
Vol 14 (3) ◽  
pp. 302-317 ◽  
Author(s):  
Francesca Fanelli ◽  
Cristina Menziani ◽  
Alexander Scheer ◽  
Susanna Cotecchia ◽  
Pier G. De Benedetti
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Adrenergic Receptor ◽  
Receptor Activation ◽  
Dynamics Simulation

scholarly journals Probing the Structural Basis of Citrus Phytochrome B using Computational Modelling and Molecular Dynamics Simulation Approaches

2021 ◽  
pp. 116895
Author(s):  
Muhammad Tahir ul Qamar ◽  
Muhammad Usman Mirza ◽  
Jia-Ming Song ◽  
Muhammad Junaid Rao ◽  
Xitong Zhu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Computational Modelling ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Phytochrome B

scholarly journals HDX-MS Combining Molecular Dynamics Simulation Reveals Structural Basis of Transcriptional Coactivator PC4 Binding to a Platinum Crosslinked Double-Stranded DNA

2021 ◽  
Author(s):  
Yuanyuan Wang ◽  
Zhifeng Du ◽  
Lifang Chen ◽  
Yao Zhao ◽  
Wei Zheng ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Dna Damage ◽  
Molecular Dynamics Simulation ◽  
Cellular Response ◽  
Minor Groove ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Future Research ◽  
Deuterium Uptake ◽  
Hdx Ms

<p>Human nuclear protein positive cofactor PC4 is a DNA-binding protein, and plays an important role in the early response to DNA damage by recognizing single-stranded oligodeoxynucleotide domain and facilitating the subsequent steps of DNA repair. Our group previously discovered that PC4 selectively binds to a double-stranded oligodeoxynucleotide (dsODN) damaged by a trans-platinum anticancer complex, trans-[PtCl2(NH3)(thiazole)] (trans-PtTz). However, the molecular basis of this unique recognition and interaction remained unclear. In this work, amide hydrogen/deuterium exchange mass spectrometry (HDX-MS) was applied to dissect the interaction interface between PC4 and a 15-mer double-stranded oligodeoxynucleotide crosslinked by trans-PtTz (trans-PtTz-dsODN). Global deuterium uptake suggested a 1:1 binding stoichiometry of PC4 to trans-PtTz-dsODN. Local deuterium uptake revealed that the flexible N-terminal loop and the β3 – β5-sheet played key roles in the recognition and interaction between PC4 and trans-PtTz-dsODN. In order to locate the key amino acid residues, molecular dynamics simulation was employed, demonstrating that PC4 binds to the trans-PtTz-dsODN at the minor groove via strong H-bonds with the nucleobases of the complementary strand. The minor groove width was broadened to adapt for the binding of PC4. Arg86 residue in PC4 was shown to dominate the recognition and interaction, which was verified by electrophoretic mobility shift assays. This work profiles the detailed interaction mechanism of PC4 with trans-PtTz damaged dsODN, and the combination use of HDX-MS and molecular dynamics simulation provides a new paradigm for the future research of the cellular response to the platinum induced DNA damage.</p>

scholarly journals HDX-MS Combining Molecular Dynamics Simulation Reveals Structural Basis of Transcriptional Coactivator PC4 Binding to a Platinum Crosslinked Double-Stranded DNA

2021 ◽  
Author(s):  
Yuanyuan Wang ◽  
Zhifeng Du ◽  
Lifang Chen ◽  
Yao Zhao ◽  
Wei Zheng ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Dna Damage ◽  
Molecular Dynamics Simulation ◽  
Cellular Response ◽  
Minor Groove ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Future Research ◽  
Deuterium Uptake ◽  
Hdx Ms

<p>Human nuclear protein positive cofactor PC4 is a DNA-binding protein, and plays an important role in the early response to DNA damage by recognizing single-stranded oligodeoxynucleotide domain and facilitating the subsequent steps of DNA repair. Our group previously discovered that PC4 selectively binds to a double-stranded oligodeoxynucleotide (dsODN) damaged by a trans-platinum anticancer complex, trans-[PtCl2(NH3)(thiazole)] (trans-PtTz). However, the molecular basis of this unique recognition and interaction remained unclear. In this work, amide hydrogen/deuterium exchange mass spectrometry (HDX-MS) was applied to dissect the interaction interface between PC4 and a 15-mer double-stranded oligodeoxynucleotide crosslinked by trans-PtTz (trans-PtTz-dsODN). Global deuterium uptake suggested a 1:1 binding stoichiometry of PC4 to trans-PtTz-dsODN. Local deuterium uptake revealed that the flexible N-terminal loop and the β3 – β5-sheet played key roles in the recognition and interaction between PC4 and trans-PtTz-dsODN. In order to locate the key amino acid residues, molecular dynamics simulation was employed, demonstrating that PC4 binds to the trans-PtTz-dsODN at the minor groove via strong H-bonds with the nucleobases of the complementary strand. The minor groove width was broadened to adapt for the binding of PC4. Arg86 residue in PC4 was shown to dominate the recognition and interaction, which was verified by electrophoretic mobility shift assays. This work profiles the detailed interaction mechanism of PC4 with trans-PtTz damaged dsODN, and the combination use of HDX-MS and molecular dynamics simulation provides a new paradigm for the future research of the cellular response to the platinum induced DNA damage.</p>

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