The mechanism by which P250L mutation impairs flavivirus-NS1 dimerization: an investigation based on molecular dynamics simulations

Oliveira, Edson R. A.; Alencastro, Ricardo Bicca de; Horta, Bruno A. C.

doi:10.1007/s00249-016-1147-9

Cited by 6 publications

(7 citation statements)

References 38 publications

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“…MD simulations have also been used to investigate the interaction of lipids with nonstructural proteins from Dengue virus. , Nonstructural proteins are key viral factors that induce membrane curvature and thereby contribute to the formation of the membranous replication complex. Lin et al modeled the nonstructural protein 4A (NS4A) in a POPC lipid bilayer by combining a docking approach and MD simulations to develop a reasonable model for the structure of the membrane-embedded and attached parts of the NS4A protein .…”

Section: Viral Proteinsmentioning

confidence: 99%

Emerging Diversity in Lipid–Protein Interactions

et al. 2019

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Membrane lipids interact with proteins in a variety of ways, ranging from providing a stable membrane environment for proteins to being embedded in to detailed roles in complicated and well-regulated protein functions. Experimental and computational advances are converging in a rapidly expanding research area of lipid–protein interactions. Experimentally, the database of high-resolution membrane protein structures is growing, as are capabilities to identify the complex lipid composition of different membranes, to probe the challenging time and length scales of lipid–protein interactions, and to link lipid–protein interactions to protein function in a variety of proteins. Computationally, more accurate membrane models and more powerful computers now enable a detailed look at lipid–protein interactions and increasing overlap with experimental observations for validation and joint interpretation of simulation and experiment. Here we review papers that use computational approaches to study detailed lipid–protein interactions, together with brief experimental and physiological contexts, aiming at comprehensive coverage of simulation papers in the last five years. Overall, a complex picture of lipid–protein interactions emerges, through a range of mechanisms including modulation of the physical properties of the lipid environment, detailed chemical interactions between lipids and proteins, and key functional roles of very specific lipids binding to well-defined binding sites on proteins. Computationally, despite important limitations, molecular dynamics simulations with current computer power and theoretical models are now in an excellent position to answer detailed questions about lipid–protein interactions.

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Section: Viral Proteinsmentioning

confidence: 99%

Emerging Diversity in Lipid–Protein Interactions

et al. 2019

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“…30,31 A particular molecular mechanism was reported by classical molecular dynamics (MD) simulations, giving a probable path in the understanding of these effects. 32 On the other hand, membrane associations (specifically, with lipid rafts) of the dimeric NS1 may be affected by the absence of specific sequences in the C-terminal region. 33 The change in the capacity to interact with lipid rafts was also shown to affect infectivity for other viruses.…”

Section: ■ Introductionmentioning

confidence: 99%

“…For example, a single mutation can impact the dimerization of NS1 ZIKV by disrupting an elaborated hydrogen-bonding network across the dimer interface . Site-directed mutagenesis assays on NS1 were shown to affect dimerization, which correlates with the slow growth of the Kunjin and Murray Valley encephalitis flaviviruses. , A particular molecular mechanism was reported by classical molecular dynamics (MD) simulations, giving a probable path in the understanding of these effects . On the other hand, membrane associations (specifically, with lipid rafts) of the dimeric NS1 may be affected by the absence of specific sequences in the C-terminal region .…”

Section: Introductionmentioning

confidence: 99%

How the Strain Origin of Zika Virus NS1 Protein Impacts Its Dynamics and Implications to Their Differential Virulence

Cuevas

Silva

Etchebest

2021

J. Chem. Inf. Model.

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Viruses can impact and affect human populations in a severe way. The appropriate differentiation among several species or strains of viruses is one of the biggest challenges for virology and infectiology studies. The detection of measurables-quantified discrepancies allows for more accurate clinical diagnoses and treatments for viral diseases. In the present study, we have used a computational approach to explore the dynamical properties of the nonstructural protein 1 from two strains of Zika virus. Our results show that despite a high sequence similarity, the two viral proteins from different origins can exhibit significant dissimilar structural dynamics, which complement their reported differential virulence. The present study opens up new ways in the understanding of the infectivity for these biological entities.

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Section: Introductionmentioning

confidence: 99%

“…As a result, Oliveira et al used molecular dynamics simulations to study how a single residue change affects dimer stability. Their research reveals conformational alterations and a local network of interactions driven by a single interface residue mutation 27 . Similarly, Roy et al investigated the importance of disulphide bonds in maintaining dimeric unit stability and β-ladder domain structure using extensive molecular dynamics simulations and thermodynamic analyses 28 .…”

Section: Introductionmentioning

confidence: 99%

Membrane-binding properties of NS1 proteins from Zika and Dengue viruses: Comparative simulations in explicit bilayers reveal significant differences

Rangarajan

Sankararamakrishnan

2023

Preprint

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NS1 in flaviviruses is the only non-structural protein that is secretory and interacts with different cellular components. NS1 is localized in endoplasmic reticulum as a dimer to facilitate the viral replication. The crystal structures of NS1 homologs from zika (ZIKV) and dengue (DENV) viruses have revealed the organization of different domains in NS1 dimers. The β-roll and the connector and intertwined loop regions of wing domains of NS1 have been shown to interact with the membranes. The membrane-binding properties and the differences between ZIKV and DENV NS1 homologs in interacting with the membranes have not been investigated. In this study, we have performed molecular dynamics (MD) simulations of ZIKV and DENV NS1 systems in apo and in POPE bilayers with different cholesterol concentrations (0, 20 and 40%). In the simulations with bilayers, the NS1 protein was placed just above the membrane surface. At the end of 600 ns production runs, ZIKV NS1 inserts deeper inside the membrane compared to the DENV counterpart. The conformational landscape sampled by NS1 in the presence of membrane was analyzed. Unlike ZIKV NS1, the orientation of DENV NS1 is asymmetric in which one of the chains in dimer interacts with the membrane while the other is exposed to the solvent. The β-roll region in ZIKV NS1 penetrates beyond the headgroup region and some residues interact with the lipid acyl chains while the C-terminal region barely interacts with the headgroup. Specific residues in the intertwined region deeply penetrate inside the membrane with less interactions with water molecules. Our analysis showed that more charged residues of ZIKV NS1 are involved in stronger interactions with the headgroups than that found for DENV NS1. The role of hydrophobic and aromatic residues in interactions with acyl chain region is also evident. Presence of cholesterol affects the extent of insertion in the membrane and interaction of individual residues. This study clearly shows that the binding, insertion and interaction of ZIKV NS1 with the lipid bilayer significantly differs from its counterpart in DENV.

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The mechanism by which P250L mutation impairs flavivirus-NS1 dimerization: an investigation based on molecular dynamics simulations

Cited by 6 publications

References 38 publications

Emerging Diversity in Lipid–Protein Interactions

Emerging Diversity in Lipid–Protein Interactions

How the Strain Origin of Zika Virus NS1 Protein Impacts Its Dynamics and Implications to Their Differential Virulence

Membrane-binding properties of NS1 proteins from Zika and Dengue viruses: Comparative simulations in explicit bilayers reveal significant differences

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