scholarly journals Fine-tuning the Spike: Role of the nature and topology of the glycan shield structure and dynamics of SARS-CoV-2 S

2021 ◽  
Author(s):  
Aoife M Harbison ◽  
Carl A Fogarty ◽  
Toan K Phung ◽  
Akash Satheesan ◽  
Benjamin L. Schulz ◽  
...  
Keyword(s):  
Glycosylation Site ◽  
Fine Tuning ◽  
Type I ◽  
Functional Roles ◽  
Functional Sites ◽  
Structure And Dynamics ◽  
Fusion Glycoprotein ◽  
Sequence Reconstruction ◽  
The Stability ◽  
Dynamics Simulations

The SARS-CoV-2 spike (S) is a type I fusion glycoprotein, responsible for initiating the infection leading to COVID19. As a feature unique of SARS-CoV-2, the thick glycan shield covering the S protein is not only essential for hiding the virus from immune detection, but it also plays multiple functional roles, stabilising the S prefusion open conformation, which is competent for binding the ACE2 primary receptor, and gating the open-to-close transitions. This newly discovered functions of the glycan shield suggest the evolution of its sites of glycosylation is potentially intertwined with the evolution of the overall protein sequence to affect optimal activity. Furthermore, recent studies indicate that the occupancy and structures of SARS-CoV-2 S glycosylation depends not only on the host-cell, but also on the structural stability of the prefusion trimer; a point that raises important questions about the relative binding competence of different glycoforms. In this work we use multi-microsecond molecular dynamics simulations to characterize the structure and dynamics of different SARS-CoV-2 S models with different N-glycans at key functional sites, namely N234, N165 and N343. We also assessed the effect of a change in the SARS-CoV-2 S glycan shield topology at N370, due to the recently acquired T372A mutation. Our results indicate that the structures of the N-glycans at N234, N165 and N343 affect the stability of the active (or open) S conformation, and thus its exposure and accessibility. Furthermore, while glycosylation at N370 stabilizes the open S conformation, we find that the N370 glycan binds the closed receptor binding domain (RBD) surface, essentially tying the closed protomers together. These results suggest that the loss of the N370 glycosylation site in SARS-CoV-2 may have increased the availability of the open S form, perhaps contributing to its higher infectivity relative to CoV1 and other variants carrying the sequon. Finally, we discuss these specific changes to the topology of the SARS-CoV-2 S glycan shield through ancestral sequence reconstruction of select SARS strains and discuss how they may have evolved to affect S activity.

scholarly journals Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response

2016 ◽  
Vol 113 (16) ◽  
pp. 4326-4331 ◽  
Author(s):  
Anja Reintjes ◽  
Julian E. Fuchs ◽  
Leopold Kremser ◽  
Herbert H. Lindner ◽  
Klaus R. Liedl ◽  
...  
Keyword(s):  
Dna Binding ◽  
Stress Responses ◽  
Structural Changes ◽  
Target Genes ◽  
Direct Interaction ◽  
Type I ◽  
Critical Residue ◽  
The Stability ◽  
Dynamics Simulations ◽  
Protein Arginine Methyltransferase 1

Nuclear factor kappa B (NF-κB) is an inducible transcription factor that plays critical roles in immune and stress responses and is often implicated in pathologies, including chronic inflammation and cancer. Although much has been learned about NF-κB–activating pathways, the specific repression of NF-κB is far less well understood. Here we identified the type I protein arginine methyltransferase 1 (PRMT1) as a restrictive factor controlling TNFα-induced activation of NF-κB. PRMT1 forms a cellular complex with NF-κB through direct interaction with the Rel homology domain of RelA. We demonstrate that PRMT1 methylates RelA at evolutionary conserved R30, located in the DNA-binding L1 loop, which is a critical residue required for DNA binding. Asymmetric R30 dimethylation inhibits the binding of RelA to DNA and represses NF-κB target genes in response to TNFα. Molecular dynamics simulations of the DNA-bound RelA:p50 predicted structural changes in RelA caused by R30 methylation or a mutation that interferes with the stability of the DNA–NF-κB complex. Our findings provide evidence for the asymmetric arginine dimethylation of RelA and unveil a unique mechanism controlling TNFα/NF-κB signaling.

The Role of Hydrophobicity in the Stability and pH-Switchability of (RXDX)4 and Coumarin-RXDX Conjugate β-Sheets

2020 ◽  
Author(s):  
Ryan Weber ◽  
Martin McCullagh
Keyword(s):  
Biological Imaging ◽  
Ph Sensing ◽  
Hydrophobic Residue ◽  
Ideal Candidate ◽  
Self Assembling ◽  
Sensing Applications ◽  
Β Sheets ◽  
The Stability ◽  
Dynamics Simulations

<p>pH-switchable, self-assembling materials are of interest in biological imaging and sensing applications. Here we propose that combining the pH-switchability of RXDX (X=Ala, Val, Leu, Ile, Phe) peptides and the optical properties of coumarin creates an ideal candidate for these materials. This suggestion is tested with a thorough set of all-atom molecular dynamics simulations. We first investigate the dependence of pH-switchabiliy on the identity of the hydrophobic residue, X, in the bare (RXDX)<sub>4</sub> systems. Increasing the hydrophobicity stabilizes the fiber which, in turn, reduces the pH-switchabilty of the system. This behavior is found to be somewhat transferable to systems in which a single hydrophobic residue is replaced with a coumarin containing amino acid. In this case, conjugates with X=Ala are found to be unstable and both pHs while conjugates with X=Val, Leu, Ile and Phe are found to form stable β-sheets at least at neutral pH. The (RFDF)<sub>4</sub>-coumarin conjugate is found to have the largest relative entropy value of 0.884 +/- 0.001 between neutral and acidic coumarin ordering distributions. Thus, we posit that coumarin-(RFDF)<sub>4</sub> containing peptide sequences are ideal candidates for pH-sensing bioelectronic materials.</p>

scholarly journals Inosine in Biology and Disease

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 600
Author(s):  
Sundaramoorthy Srinivasan ◽  
Adrian Gabriel Torres ◽  
Lluís Ribas de Pouplana
Keyword(s):  
Human Health ◽  
Purine Biosynthesis ◽  
Messenger Rnas ◽  
Transfer Rnas ◽  
Functional Roles ◽  
Codon Recognition ◽  
Wobble Position ◽  
Biosynthesis Gene ◽  
The Stability ◽  
Cell Signaling Pathways

The nucleoside inosine plays an important role in purine biosynthesis, gene translation, and modulation of the fate of RNAs. The editing of adenosine to inosine is a widespread post-transcriptional modification in transfer RNAs (tRNAs) and messenger RNAs (mRNAs). At the wobble position of tRNA anticodons, inosine profoundly modifies codon recognition, while in mRNA, inosines can modify the sequence of the translated polypeptide or modulate the stability, localization, and splicing of transcripts. Inosine is also found in non-coding and exogenous RNAs, where it plays key structural and functional roles. In addition, molecular inosine is an important secondary metabolite in purine metabolism that also acts as a molecular messenger in cell signaling pathways. Here, we review the functional roles of inosine in biology and their connections to human health.

scholarly journals Hot-Wire Laser-Directed Energy Deposition: Process Characteristics and Benefits of Resistive Pre-Heating of the Feedstock Wire

Metals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 634
Author(s):  
Agnieszka Kisielewicz ◽  
Karthikeyan Thalavai Pandian ◽  
Daniel Sthen ◽  
Petter Hagqvist ◽  
Maria Asuncion Valiente Bermejo ◽  
...  
Keyword(s):  
Heat Input ◽  
Energy Deposition ◽  
Fine Tuning ◽  
Hot Wire ◽  
Process Stability ◽  
Electrical Signals ◽  
Melt Pool ◽  
Directed Energy Deposition ◽  
Directed Energy ◽  
The Stability

This study investigates the influence of resistive pre-heating of the feedstock wire (here called hot-wire) on the stability of laser-directed energy deposition of Duplex stainless steel. Data acquired online during depositions as well as metallographic investigations revealed the process characteristic and its stability window. The online data, such as electrical signals in the pre-heating circuit and images captured from side-view of the process interaction zone gave insight on the metal transfer between the molten wire and the melt pool. The results show that the characteristics of the process, like laser-wire and wire-melt pool interaction, vary depending on the level of the wire pre-heating. In addition, application of two independent energy sources, laser beam and electrical power, allows fine-tuning of the heat input and increases penetration depth, with little influence on the height and width of the beads. This allows for better process stability as well as elimination of lack of fusion defects. Electrical signals measured in the hot-wire circuit indicate the process stability such that the resistive pre-heating can be used for in-process monitoring. The conclusion is that the resistive pre-heating gives additional means for controlling the stability and the heat input of the laser-directed energy deposition.

Study on the characteristics of secondary arc current of UHV high compensation degree TCSC line under the fine-tuning mode

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Baina He ◽  
Yadi Xie ◽  
Jingru Zhang ◽  
Nirmal-Kumar C. Nair ◽  
Xingmin He ◽  
...  
Keyword(s):  
Transmission Line ◽  
Transmission Lines ◽  
Stability Margin ◽  
Transmission Capacity ◽  
Fine Tuning ◽  
Series Compensation ◽  
Arc Current ◽  
Compensation Device ◽  
The Stability ◽  
Recovery Voltage

Abstract In the transmission line, the series compensation device is often used to improve the transmission capacity. However, when the fixed series capacitor (FSC) is used in high compensation series compensation device, the stability margin cannot meet the requirements. Therefore, thyristor controlled series compensator (TCSC) is often installed in transmission lines to improve the transmission capacity of the line and the stability of the system. For cost considerations, the hybrid compensation mode of FSC and TCSC is often adopted. However, when a single-phase grounding fault occurs in a transmission line with increased series compensation degree, the unreasonable distribution of FSC and TCSC will lead to the excessive amplitude of secondary arc current, which is not conducive to rapid arc extinguishing. To solve this problem, this paper is based on 1000 kV Changzhi-Nanyang-Jingmen UHV series compensation transmission system, using PSCAD simulation program to established UHV series compensation simulation model, The variation law of secondary arc current and recovery voltage during operation in fine tuning mode after adding TCSC to UHV transmission line is analyzed, and the effect of increasing series compensation degree on secondary arc current and recovery voltage characteristics is studied. And analyze the secondary arc current and recovery voltage when using different FSC and TCSC series compensation degree schemes, and get the most reasonable series compensation configuration scheme. The results show that TCSC compensation is more beneficial to arc extinguishing under the same series compensation. Compared with several series compensation schemes, it is found that with the increase of the proportion of TCSC, the amplitude of secondary arc current and recovery voltage vary greatly. Considering various factors, the scheme that is more conducive to accelerating arc extinguishing is chosen.

scholarly journals Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

2021 ◽  
Vol 22 (5) ◽  
pp. 2732
Author(s):  
Nadine Reichhart ◽  
Vladimir M. Milenkovic ◽  
Christian H. Wetzel ◽  
Olaf Strauß
Keyword(s):  
Transmembrane Protein ◽  
Functional Characterization ◽  
Missense Mutations ◽  
Mutant Proteins ◽  
Functional Consequences ◽  
New Perspective ◽  
The Stability ◽  
Dynamics Simulations ◽  
And Function

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.

The possibility of a stable flat dark energy-dominated Swiss-cheese brane-world universe

2020 ◽  
Vol 17 (05) ◽  
pp. 2050075
Author(s):  
Nasr Ahmed ◽  
Kazuharu Bamba ◽  
F. Salama
Keyword(s):  
Dark Energy ◽  
Cosmological Constant ◽  
Cosmological Models ◽  
Brane World ◽  
Fine Tuning ◽  
Energy Conditions ◽  
Late Time ◽  
Swiss Cheese ◽  
Black Strings ◽  
The Stability

In this paper, we study the possibility of obtaining a stable flat dark energy-dominated universe in a good agreement with observations in the framework of Swiss-cheese brane-world cosmology. Two different brane-world cosmologies with black strings have been introduced for any cosmological constant [Formula: see text] using two empirical forms of the scale factor. In both models, we have performed a fine-tuning between the brane tension and the cosmological constant so that the Equation of state (EoS) parameter [Formula: see text] for the current epoch, where the redshift [Formula: see text]. We then used these fine–tuned values to calculate and plot all parameters and energy conditions. The deceleration–acceleration cosmic transition is allowed in both models, and the jerk parameter [Formula: see text] at late-times. Both solutions predict a future dark energy-dominated universe in which [Formula: see text] with no crossing to the phantom divide line. While the pressure in the first solution is always negative, the second solution predicts a better behavior of cosmic pressure where the pressure is negative only in the late-time accelerating era but positive in the early-time decelerating era. Such a positive-to-negative transition in the evolution of pressure helps to explain the cosmic deceleration–acceleration transition. Since black strings have been proved to be unstable by some authors, this instability can actually reflect doubts on the stability of cosmological models with black strings (Swiss-cheese type brane-worlds cosmological models). For this reason, we have carefully investigated the stability through energy conditions and sound speed. Because of the presence of quadratic energy terms in Swiss-cheese type brane-world cosmology, we have tested the new nonlinear energy conditions in addition to the classical energy conditions. We have also found that a negative tension brane is not allowed in both models of the current work as the energy density will no longer be well defined.

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