Molecular dynamics exploration of the binding mechanism and properties of single-walled carbon nanotube to WT and mutant VP35 FBP region of Ebola virus

Zhang, Yanjun; Ding, Jingna; Zhong, Hui; Sun, Changzheng; Han, Ju‐Guang

doi:10.1007/s10867-016-9440-5

Cited by 9 publications

(5 citation statements)

References 35 publications

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“…However, the actual importance of this amino acid residue had not been evaluated in biological assays in vitro. In this study, we provide direct evidence that P293 is important for both polymerase cofactor function and suppression of IFN production, supporting the previous in silico studies that predicted the functional importance of this amino acid position [31][32][33]. Interestingly, the VP35 functions were impaired even by the P293 mutants with amino acid substitutions that had little effect on the patch #3 hydrophobicity (Figure 2).…”

Section: Discussionsupporting

confidence: 88%

“…In this study, we have shown for the first time that P293 of VP35 contributes to polymerase cofactor activity and IFN-β suppression. Using computer analyses, the P293 residue has been predicted to be important for the interaction with small molecule compounds that may potentially inhibit VP35 functions [31][32][33]. However, the actual importance of this amino acid residue had not been evaluated in biological assays in vitro.…”

Section: Discussionmentioning

confidence: 99%

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Functional Importance of Hydrophobic Patches on the Ebola Virus VP35 IFN-Inhibitory Domain

Kasajima

Matsuno

Miyamoto

et al. 2021

Viruses

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Viral protein 35 (VP35) of Ebola virus (EBOV) is a multifunctional protein that mainly acts as a viral polymerase cofactor and an interferon antagonist. VP35 interacts with the viral nucleoprotein (NP) and double-stranded RNA for viral RNA transcription/replication and inhibition of type I interferon (IFN) production, respectively. The C-terminal portion of VP35, which is termed the IFN-inhibitory domain (IID), is important for both functions. To further identify critical regions in this domain, we analyzed the physical properties of the surface of VP35 IID, focusing on hydrophobic patches, which are expected to be functional sites that are involved in interactions with other molecules. Based on the known structural information of VP35 IID, three hydrophobic patches were identified on its surface and their biological importance was investigated using minigenome and IFN-β promoter-reporter assays. Site-directed mutagenesis revealed that some of the amino acid substitutions that were predicted to disrupt the hydrophobicity of the patches significantly decreased the efficiency of viral genome replication/transcription due to reduced interaction with NP, suggesting that the hydrophobic patches might be critical for the formation of a replication complex through the interaction with NP. It was also found that the hydrophobic patches were involved in the IFN-inhibitory function of VP35. These results highlight the importance of hydrophobic patches on the surface of EBOV VP35 IID and also indicate that patch analysis is useful for the identification of amino acid residues that directly contribute to protein functions.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Functional Importance of Hydrophobic Patches on the Ebola Virus VP35 IFN-Inhibitory Domain

Kasajima

Matsuno

Miyamoto

et al. 2021

Viruses

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“…To estimate the binding energy between lysozyme and Gd@C 60 and their components, we carried out a MM-GBSA analysis of the trajectory. This methodology has provided valuable information to estimate the interaction between proteins and carbon nanomaterials. − …”

Section: Results and Discussionmentioning

confidence: 99%

Interactions between Endohedral Metallofullerenes and Proteins: The Gd@C₆₀–Lysozyme Model

et al. 2018

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Endohedral metallofullerenes (EMFs) have great potential as radioisotope carriers for nuclear medicine and as contrast agents for X-ray and magnetic resonance imaging. EMFs have still important restrictions for their use due to low solubility in physiological environments, low biocompatibility, nonspecific cellular uptake, and a strong dependence of their peculiar properties on physiological parameters, such as pH and salt content. Conjugation of the EMFs with proteins can overcome many of these limitations. Here we investigated the thermodynamics of binding of a model EMF (Gd@C 60 ) with a protein (lysozyme) that is known to act as a host for the empty fullerene. As a rule, even if the shape of an EMF is exactly the same as that of the related fullerene, the interactions with a protein are significantly different. The estimated interaction energy (Δ G binding ) between Gd@C 60 and lysozyme is −18.7 kcal mol –1 , suggesting the possibility of using proteins as supramolecular carriers for EMFs. π–π stacking, hydrophobic interactions, surfactant-like interactions, and electrostatic interactions govern the formation of the hybrid between Gd@C 60 and lysozyme. The comparison of the energy contributions to the binding between C 60 or Gd@C 60 and lysozyme suggests that, although shape complementarity remains the driving force of the binding, the presence of electron transfer from the gadolinium atom to the carbon cage induces a charge distribution on the fullerene cage that strongly affects its interaction with the protein.

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“…In the third step, the system was minimized at a constant temperature of 300 K and a constant pressure of 1 atm for another 50 ps. In the last step, the whole system was equilibrated at the NPT ensemble for 500 ps without any restraints . In the MD simulation, the temperature was set to 300 K, and periodic boundary condition was applied to all dimensions.…”

Section: Methodsmentioning

confidence: 99%

“…In the last step, the whole system was equilibrated at the NPT ensemble for 500 ps without any restraints. 29 In the MD simulation, the temperature was set to 300 K, and periodic boundary condition was applied to all dimensions. The dsRNA-free and dsRNA-binding trajectories were run for 520 ns (WT-free), 300 ns (R312A-free), 250 ns (R322A-free), 220 ns (K339Afree), 270 ns (R312A/R322A-free), 380 ns (WT-dsRNA), 410 ns (R312A-dsRNA), 620 ns (R322A-dsRNA), 300 ns (K339A-dsRNA), and 620 ns (R312A/R322A-dsRNA), respectively, when all the systems have achieved equilibrium.…”

Section: Molecular Dynamics (Md) Simulationmentioning

confidence: 99%

Exploration micromechanism of VP35 IID interaction and recognition dsRNA: A molecular dynamics simulation

et al. 2017

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Multifunctional viral protein (VP35) encoded by the highly pathogenic Ebola viruses (EBOVs) can antagonize host double-stranded RNA (dsRNA) sensors and immune response because of the simultaneous recognition of dsRNA backbone and blunt ends. Mutation of select hydrophobic conserved basic residues within the VP35 inhibitory domain (IID) abrogates its dsRNA-binding activity, and impairs VP35-mediated interferon (IFN) antagonism. Herein the detailed binding mechanism between dsRNA and WT, single mutant, and double mutant were investigated by all-atom molecular dynamics (MD) simulation and binding energy calculation. R312A/R322A double mutations results in a completely different binding site and orientation upon the structure analyses. The calculated binding free energy results reveal that R312A, R322A, and K339A single mutations decrease the binding free energies by 17.82, 13.18, and 13.68 kcal mol , respectively. The binding energy decomposition indicates that the strong binding affinity of the key residues is mainly due to the contributions of electrostatic interactions in the gas phase, where come from the positively charged side chain and the negatively charged dsRNA backbone. R312A, R322A, and K339A single mutations have no significant effect on VP35 IID conformation, but the mutations influence the contributions of electrostatic interactions in the gas phase. The calculated results reveal that end-cap residues which mainly contribute VDW interactions can recognize and capture dsRNA blunt ends, and the central basic residues (R312, R322, and K339) which mainly contribute favorable electrostatic interactions with dsRNA backbone can fix dsRNA binding site and orientation. Proteins 2017; 85:1008-1023. © 2017 Wiley Periodicals, Inc.

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Molecular dynamics exploration of the binding mechanism and properties of single-walled carbon nanotube to WT and mutant VP35 FBP region of Ebola virus

Cited by 9 publications

References 35 publications

Functional Importance of Hydrophobic Patches on the Ebola Virus VP35 IFN-Inhibitory Domain

Functional Importance of Hydrophobic Patches on the Ebola Virus VP35 IFN-Inhibitory Domain

Interactions between Endohedral Metallofullerenes and Proteins: The Gd@C₆₀–Lysozyme Model

Exploration micromechanism of VP35 IID interaction and recognition dsRNA: A molecular dynamics simulation

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Molecular dynamics exploration of the binding mechanism and properties of single-walled carbon nanotube to WT and mutant VP35 FBP region of Ebola virus

Cited by 9 publications

References 35 publications

Functional Importance of Hydrophobic Patches on the Ebola Virus VP35 IFN-Inhibitory Domain

Functional Importance of Hydrophobic Patches on the Ebola Virus VP35 IFN-Inhibitory Domain

Interactions between Endohedral Metallofullerenes and Proteins: The Gd@C60–Lysozyme Model

Exploration micromechanism of VP35 IID interaction and recognition dsRNA: A molecular dynamics simulation

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Interactions between Endohedral Metallofullerenes and Proteins: The Gd@C₆₀–Lysozyme Model