scholarly journals Molecular Dynamics of SARS-CoV-2 Nsp1 Structural Changes Associated with Variant Mutations

2021 ◽  
Author(s):  
Shokouh Rezaei ◽  
Yahya Sefidbakht ◽  
Filipe Pereira
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Structural Changes ◽  
Structure And Function ◽  
Dynamics Simulation ◽  
Structural Protein ◽  
Wild Type ◽  
Deletion Mutations ◽  
And Function

Abstract SARS-CoV-2 non-structural protein 1 (Nsp1) is a virulence factor that inhibits the translation of host mRNAs and interact with viral RNA. Despite the relevance of Nsp1, few studies have been conducted to understand the effect of mutations on Nsp1 structure and function. Here, we provide a molecular dynamics simulation of SARS-CoV-2 Nsp1, wild type and variants. We found that SARS-CoV-2 Nsp1 has a more Rg value than SARS-CoV-1 Nsp1, with indicate an effect on the folding protein. This result suggest that SARS-CoV-2 Nsp1 can more easily approach the active site of the ribosome compared to SARS-CoV-1 Nsp1. In addition, we found that the C-terminal of the SARS-CoV-2 Nsp1, in particular residues 164 to 170, are more flexible than other regions of SARS-CoV-2 Nsp1 and SARS-CoV-1 Nsp1, confirming the role of this region in the interaction with the 40S subunit. Moreover, multiple deletion mutations have been found in the N/C-terminal of the SARS-CoV-2 Nsp1, which seems the effect of SARS-CoV-2 Nsp1 multiple deletions is greater than that of substitutions. Among all deletions, D156-158 and D80-90 may destabilize the protein structure and possibly increase the virulence of the SARS-CoV-2. Overall, our findings reinforce the importance of studying Nsp1 conformational changes in new variants and its effect on virulence of SARS-CoV-2.

scholarly journals Surface-Exposed Adeno-Associated Virus Vp1-NLS Capsid Fusion Protein Rescues Infectivity of Noninfectious Wild-Type Vp2/Vp3 and Vp3-Only Capsids but Not That of Fivefold Pore Mutant Virions

2007 ◽  
Vol 81 (15) ◽  
pp. 7833-7843 ◽  
Author(s):  
Joshua C. Grieger ◽  
Jarrod S. Johnson ◽  
Brittney Gurda-Whitaker ◽  
Mavis Agbandje-McKenna ◽  
R. Jude Samulski
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Wild Type ◽  
Dot Blot ◽  
Adeno Associated Virus ◽  
N Terminus ◽  
Localization Signal ◽  
Significant Effort

ABSTRACT Over the past 2 decades, significant effort has been dedicated to the development of adeno-associated virus (AAV) as a vector for human gene therapy. However, understanding of the virus with respect to the functional domains of the capsid remains incomplete. In this study, the goal was to further examine the role of the unique Vp1 N terminus, the N terminus plus the recently identified nuclear localization signal (NLS) (J. C. Grieger, S. Snowdy, and R. J. Samulski, J. Virol 80:5199-5210, 2006), and the virion pore at the fivefold axis in infection. We generated two Vp1 fusion proteins (Vp1 and Vp1NLS) linked to the 8-kDa chemokine domain of rat fractalkine (FKN) for the purpose of surface exposure upon assembly of the virion, as previously described (K. H. Warrington, Jr., O. S. Gorbatyuk, J. K. Harrison, S. R. Opie, S. Zolotukhin, and N. Muzyczka, J. Virol 78:6595-6609, 2004). The unique Vp1 N termini were found to be exposed on the surfaces of these capsids and maintained their phospholipase A2 (PLA2) activity, as determined by native dot blot Western and PLA2 assays, respectively. Incorporation of the fusions into AAV type 2 capsids lacking a wild-type Vp1, i.e., Vp2/Vp3 and Vp3 capsid only, increased infectivity by 3- to 5-fold (Vp1FKN) and 10- to 100-fold (Vp1NLSFKN), respectively. However, the surface-exposed fusions did not restore infectivity to AAV virions containing mutations at a conserved leucine (Leu336Ala, Leu336Cys, or Leu336Trp) located at the base of the fivefold pore. EM analyses suggest that Leu336 may play a role in global structural changes to the virion directly impacting downstream conformational changes essential for infectivity and not only have local effects within the pore, as previously suggested.

scholarly journals Conformational effects of Lys191 in the human GnRH receptor: mutagenesis and molecular dynamics simulations studies

2009 ◽  
Vol 201 (2) ◽  
pp. 297-307 ◽  
Author(s):  
Eduardo Jardón-Valadez ◽  
Arturo Aguilar-Rojas ◽  
Guadalupe Maya-Núñez ◽  
Alfredo Leaños-Miranda ◽  
Ángel Piñeiro ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Dynamic Behavior ◽  
Gnrh Receptor ◽  
Receptor Trafficking ◽  
Wild Type ◽  
Conformational Effects ◽  
Dynamics Simulations ◽  
And Function

In the present study, we analyzed the role of Lys191 on function, structure, and dynamic behavior of the human GnRH receptor (hGnRHR) and the formation of the Cys14–Cys200 bridge, which is essential for receptor trafficking to the plasma membrane. Several mutants were studied; mutants lacked either the Cys14–Cys200 bridge, Lys191 or both. The markedly reduced expression and function of a Cys14Ser mutant lacking the 14–200 bridge, was nearly restored to wild-type/ΔLys191 levels upon deletion of Lys191. Lys191 removal resulted in changes in the dynamic behavior of the mutants as disclosed by molecular dynamics simulations: the distance between the sulfur- (or oxygen-) sulfur groups of Cys (or Ser)14 and Cys200 was shorter and more constant, and the conformation of the NH2-terminus and the exoloop 2 exhibited fewer fluctuations than when Lys191 was present. These data provide novel information on the role of Lys191 in defining an optimal configuration for the hGnRHR intracellular trafficking and function.

scholarly journals Role of Wybutosine and Mg2+ Ions in Modulating the Structure and Function of tRNAPhe: A Molecular Dynamics Study

ACS Omega ◽  
2019 ◽  
Vol 4 (25) ◽  
pp. 21327-21339
Author(s):  
Prayagraj M. Fandilolu ◽  
Asmita S. Kamble ◽  
Ambika S. Dound ◽  
Kailas D. Sonawane
Keyword(s):  
Molecular Dynamics ◽  
Structure And Function ◽  
And Function

scholarly journals Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis

2005 ◽  
Vol 25 (14) ◽  
pp. 6225-6234 ◽  
Author(s):  
Feng Li ◽  
Yunyue Wang ◽  
Karen I. Zeller ◽  
James J. Potter ◽  
Diane R. Wonsey ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Structure And Function ◽  
Wild Type ◽  
Primary Hepatocytes ◽  
Mitochondrial Mass ◽  
Mitochondrial Structure ◽  
Direct Binding ◽  
Rat Fibroblasts ◽  
And Function

ABSTRACT Although several genes involved in mitochondrial function are direct Myc targets, the role of Myc in mitochondrial biogenesis has not been directly established. We determined the effects of ectopic Myc expression or the loss of Myc on mitochondrial biogenesis. Induction of Myc in P493-6 cells resulted in increased oxygen consumption and mitochondrial mass and function. Conversely, compared to wild-type Myc fibroblasts, Myc null rat fibroblasts have diminished mitochondrial mass and decreased number of normal mitochondria. Reconstitution of Myc expression in Myc null fibroblasts partially restored mitochondrial mass and function and normal-appearing mitochondria. Concordantly, we also observed in primary hepatocytes that acute deletion of floxed murine Myc by Cre recombinase resulted in diminished mitochondrial mass in primary hepatocytes. Our microarray analysis of genes responsive to Myc in human P493-6 B lymphocytes supports a role for Myc in mitochondrial biogenesis, since genes involved in mitochondrial structure and function are overrepresented among the Myc-induced genes. In addition to the known direct binding of Myc to many genes involved in mitochondrial structure and function, we found that Myc binds the TFAM gene, which encodes a key transcriptional regulator and mitochondrial DNA replication factor, both in P493-6 lymphocytes with high ectopic MYC expression and in serum-stimulated primary human 2091 fibroblasts with induced endogenous MYC. These observations support a pivotal role for Myc in regulating mitochondrial biogenesis.

scholarly journals Influence of Disulfide Bridge on the Structural Stability of Human Neuroglobin: A Molecular Dynamics Simulation Using Latest Data Entry

2016 ◽  
Vol 26 (2) ◽  
pp. 151
Author(s):  
Bui Thi Le Quyen ◽  
Nguyen Thi Lam Hoai ◽  
Ngo Van Thanh
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Structural Stability ◽  
Data Entry ◽  
Disulfide Bridge ◽  
Dynamics Simulation ◽  
Wild Type ◽  
Heme Group ◽  
Classical Simulation

In this paper, we investigated the role of the disulfide bridge in the structural stability of wild-type human neuroglobin. The classical simulation of the neuroglobin without the disulfide bridge was performed for a long simulation run of 240~ns   using a new parameter set of Gromos96 force field and the latest data entry as the initial topologies. We used the analyzed data of original neuroglobin with the remained disulfide bridge to compare to the ones from this simulation. Our results showed that, the structure of neuroglobin was still very stable although the disulfide bridge was absent. There was only a few residues in B and C helices having a higher mobility. The most interesting result we obtained was that the increasing distance between the distal histidine and heme group could allow oxygen to bind more easily.

scholarly journals The Impact of Mutation L138F/L210F on the Orai Channel: A Molecular Dynamics Simulation Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoqian Zhang ◽  
Hua Yu ◽  
Xiangdong Liu ◽  
Chen Song
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Calcium Release ◽  
Hydrophobic Interactions ◽  
Dynamics Simulation ◽  
Wild Type ◽  
Hydrophobic Region ◽  
In The Wild ◽  
Dynamics Simulations ◽  
The Impact

The calcium release-activated calcium channel, composed of the Orai channel and the STIM protein, plays a crucial role in maintaining the Ca2+ concentration in cells. Previous studies showed that the L138F mutation in the human Orai1 creates a constitutively open channel independent of STIM, causing severe myopathy, but how the L138F mutation activates Orai1 is still unclear. Here, based on the crystal structure of Drosophila melanogaster Orai (dOrai), molecular dynamics simulations for the wild-type (WT) and the L210F (corresponding to L138F in the human Orai1) mutant were conducted to investigate their structural and dynamical properties. The results showed that the L210F dOrai mutant tends to have a more hydrated hydrophobic region (V174 to F171), as well as more dilated basic region (K163 to R155) and selectivity filter (E178). Sodium ions were located deeper in the mutant than in the wild-type. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously unobserved feature, was found to result in the opening of the K163 gate through hydrophobic interactions. At the same time, a counter-clockwise rotation of F171 occurred more frequently in the mutant, resulting in a wider hydrophobic gate with more hydration. Ultimately, the opening of the two gates may facilitate the opening of the Orai channel independent of STIM.

scholarly journals In silico tracking of SARS-CoV-2 Nsp1 structural variants in helix-turn-helix motif

2021 ◽  
Author(s):  
Shokouh Rezaei ◽  
Filipe Pereira ◽  
yahya sefidbakht
Keyword(s):  
Conformational Changes ◽  
Mrna Translation ◽  
Dynamics Simulation ◽  
Translation Efficiency ◽  
Structural Protein ◽  
Compact Structure ◽  
Helix Loop Helix ◽  
Host Virus Interactions ◽  
And Function ◽  
Virus Interactions

SARS-CoV-2 non-structural protein 1 (Nsp1) is a virulence factor that inhibits the innate immune response and translation of host mRNAs. Despite the relevance of Nsp1, few studies have been conducted to understand the effect of mutations on Nsp1 structure and function. Here, we provide a molecular dynamics simulation of SARS-CoV-2 and SARS-CoV-1 Nsp1 conformational changes. Our data supports the idea that SARS-CoV-2 Nsp1 has a less compact structure than SARS-CoV-1 Nsp1. Moreover, several mutations in the helix-loop-helix motif of Nsp1 C-terminal that may affect the interactions of the Nsp1-ribosome complex were investigated. Disordered regions in Nsp1 probably affect host-virus interactions, cross-species transmission, and virus-host range. Overall, these findings reinforce the importance of studying Nsp1 conformational changes in new variants and its effect on virulence of SARS-CoV-2, by altering inhibition potency of host mRNA translation efficiency.

scholarly journals Understanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sangho Ji ◽  
Wonjin Yang ◽  
Wookyung Yu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Structural Changes ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Interaction Network ◽  
Dynamics Simulation ◽  
Activation Mechanism ◽  
Toggle Switch

AbstractThe cannabinoid receptor 1 (CB1) is a class A G-protein coupled receptor (GPCR) that can exert various effects on the human body through the endocannabinoid system. Understanding CB1 activation has many benefits for the medical use of cannabinoids. A previous study reported that CB1 has two notable residues referred to as the toggle switch, F3.36 and W6.48, which are important for its activation mechanism. We performed a molecular dynamics simulation with a mutation in the toggle switch to examine its role in active and inactive states. We also examined structural changes, the residue–residue interaction network, and the interaction network among helices and loops of wildtype and mutant CB1 for both activation states. As a result, we found that the energetic changes in the hydrogen-bond network of the Na+ pocket, extracellular N-terminus–TM2–ECL1–TM3 interface including D2.63–K3.28 salt-bridge, and extracellular ECL2–TM5–ECL3–TM6 interface directly linked to the toggle switch contribute to the stability of CB1 by the broken aromatic interaction of the toggle switch. It makes the conformation of inactive CB1 receptor to be unstable. Our study explained the role of the toggle switch regarding the energetic interactions related to the Na+ pocket and extracellular loop interfaces, which could contribute to a better understanding of the activation mechanism of CB1.

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