scholarly journals Immune escape facilitation by mutations of epitope residues in RdRp of SARS-CoV-2

2021 ◽  
Author(s):  
Aayatti Mallick Gupta ◽  
Sasthi Charan Mandal ◽  
Jaydeb Chakrabarti ◽  
Sukhendu Mandal
Keyword(s):  
Conformational Changes ◽  
Md Simulation ◽  
Immune Escape ◽  
Dihedral Angles ◽  
Radius Of Gyration ◽  
Simulation Studies ◽  
Epitope Region ◽  
Naturally Occurring ◽  
Intramolecular Hydrogen ◽  
Opening Up

SARS-CoV-2 has considerably higher mutation rate. SARS-CoV-2 possesses a RNA dependent RNA polymerase (RdRp) which helps to replicate its genome. The mutation P323L in RdRp is associated with the loss of a particular epitope (321-327) from this protein which may influence the pathogenesis of the concern SARS-CoV-2 through the development of antibody escape variants. We consider the effect of mutations in some of the epitope regions including the naturally occurring mutation P323L on the structure of the epitope and their interface with paratope using all-atom molecular dynamics (MD) simulation studies. P323L mutations cause conformational changes in the epitope region by opening up the region associated with increase in the radius of gyration and intramolecular hydrogen bonds, making the region less accessible. Moreover, the fluctuations in the dihedral angles in the epitope:paratope (IgG) interface increase which destabilize the interface. Such mutations may help in escaping antibody mediated immunity of the host.

Molecular Docking and Interaction Studies of Identified Abscisic Acid Receptors in Oryza sativa: An In-Silico Perspective on Comprehending Stress Tolerance Mechanisms

2021 ◽  
Vol 23 ◽  
Author(s):  
Vidya Niranjan ◽  
Amulya Rao ◽  
B Janaki ◽  
Akshay Uttarkar ◽  
Anagha S Setlur ◽  
...  
Keyword(s):  
Oryza Sativa ◽  
Abscisic Acid ◽  
Molecular Docking ◽  
Conformational Changes ◽  
Docking Studies ◽  
Protein Docking ◽  
Ligand Docking ◽  
Simulation Studies ◽  
Naturally Occurring ◽  
Aba Receptors

Background: Abiotic stresses affect plants in several ways and as such, phytohormones such as abscisic acid (ABA) play an important role in conferring tolerance towards these stresses. Hence, to comprehend the role of ABA and its interaction with receptors of the plants, a thorough investigation is essential. Aim: The current study aimed to identify the ABA receptors in Oryza sativa, to find the receptor that binds best with ABA and to examine the mutations present to help predict better binding of the receptors with ABA Methods: Protein sequences of twelve PYL (Pyrabactin resistance 1) and seven PP2C (type 2C protein phosphatase) receptors were retrieved from Rice Annotation Project database and their 3D structures were predicted using RaptorX. Protein-ligand molecular docking studies between PYL and ABA was performed using AutoDock 1.5.6, followed by 100ns molecular dynamic simulation studies using Desmond to determine the acceptable conformational changes after docking via root mean square deviation RMSD plot analysis. Protein-protein docking was then carried out in three sets: PYL-PP2Cs, PYL-ABA-PP2C and PYL(mut)-ABA-PP2C to scrutinize changes in structural conformations and binding energies between complexes. The amino acids of interest were mapped at its respective genomic coordinates using SNP-seek database to ascertain if there were any naturally occurring single nucleotide polymorphisms (SNPs) responsible for triggering rice PYLs mutations Results: Initial protein-ligand docking studies revealed good binding between the complexes, wherein PYL6-ABA complex showed the best energy of -8.15 kcal/mol. The 100ns simulation studies revealed changes in the RMSD values after docking, indicating acceptable conformational changes. Furthermore, mutagenesis study performed at specific PYL-ABA interacting residues followed by downstream PYL(mut)-ABA-PP2C protein-protein docking results after induction of mutations demonstrated a binding energy of -8.17 kcal/mol for PP2C79-PYL11-ABA complex. No naturally occurring SNPs that were responsible for triggering rice PYL mutations were identified when specific amino acid coordinates were mapped at respective genomic coordinates. Conclusion: Thus, the present study provides valuable insights on the interactions of ABA receptors in rice and induced mutations in PYL11 that can enhance the downstream interaction with PP2C

Crystalline conformation and structure of lichenan and barley β-glucan

1983 ◽  
Vol 61 (7) ◽  
pp. 1608-1616 ◽  
Author(s):  
I. Tvaroska ◽  
K. Ogawa ◽  
Y. Deslandes ◽  
R. H. Marchessault
Keyword(s):  
Cell Walls ◽  
Unit Cell ◽  
Group Symmetry ◽  
Fiber Axis ◽  
Dihedral Angles ◽  
X Ray ◽  
Naturally Occurring ◽  
C Fiber ◽  
Intramolecular Hydrogen ◽  
Helical Parameters

An investigation based on X-ray fiber diffraetion and conformational analysis methods has provided a proposed chain conformation and crystalline structure for lichenan, a poly β(1 → 3) cellotriose. The analysis of the fiber diagram of the hydrated form of lichenan led to a trigonal unit cell of dimension a = b = 9.92 Å and c (fiber axis) = 42.03 Å, with cellotriose as the asymmetric unit and six cellotriose residues per unit cell. A unit cell of the dry form is also trigonal with a = b = 9.36 Å and c = 42.03 Å. A right-handed threefold helix made up of three cellotriose residues was derived from a comparison of experimental helical parameters with isoenenergy conformational maps made by plotting dihedral angles ([Formula: see text], ψ) at the β(1 → 3) linkage. A virtual bond approach was also used to arrive at the proposed conformation which is stabilized by intramolecular hydrogen bonds between all carbohydrate units. The refinement of geometrical and packing parameters produced results consistent with an antiparallel arrangement of the two chains corresponding to a space group symmetry of P31. The naturally occurring copolysaccharides known as mixed (1 → 3) and (1 → 4) β-glucans from the cell walls of barley endosperm have been shown to crystallize in the same fashion as lichenan.

scholarly journals Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sensen Zhang ◽  
Baolei Yuan ◽  
Jordy Homing Lam ◽  
Jun Zhou ◽  
Xuan Zhou ◽  
...  
Keyword(s):  
Md Simulation ◽  
Potential Role ◽  
Md Simulations ◽  
Full Length ◽  
Inflammasome Activation ◽  
Simulation Studies ◽  
Cryo Electron Microscopy ◽  
Gating Mechanism ◽  
Atp Efflux

AbstractPannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.

THE "FOLDING" BEHAVIORS OF HOMOPOLYMERS WITH ONE END FIXED

2004 ◽  
Vol 18 (15) ◽  
pp. 2123-2139 ◽  
Author(s):  
BIN XUE ◽  
JUN WANG ◽  
WEI WANG
Keyword(s):  
Molecular Dynamics ◽  
Chain Length ◽  
Conformational Changes ◽  
Canonical Ensemble ◽  
Interaction Strength ◽  
Simulation Method ◽  
Dynamics Simulation ◽  
Radius Of Gyration ◽  
Native Conformation ◽  
Collapse Temperature

We study the "folding" behaviors of homopolymers with one end fixed. By using canonical ensemble molecular dynamics simulation method, we observe the conformational changes during folding processes. Long chains collapse to the helical nuclei, then regroup to helix from the free-end to form the compact conformations through the middle stages of helix-like coil and helix-like cone, while short chains do not apparently have the above mentioned middle stages. Through simulated annealing, the native conformation of homopolymer chain in our model is found to be helix. We show the relations between specific heat C v (T) and radius of gyration R g (T) as functions of temperature, chain length and the interaction strength, respectively. We find that these two quantities match well and can be combined to interpret the "folding" process of the homopolymer. It is found that the collapse temperature Tθ and the native-like folding temperature T f do not change with the chain length in our model, however the interaction strength affects the values of Tθ and T f .

scholarly journals Processing of RNA Containing 8-Oxo-7,8-Dihydroguanosine (8-oxoG) by the Exoribonuclease Xrn-1

2021 ◽  
Vol 8 ◽  
Author(s):  
Cheyenne N. Phillips ◽  
Shawn Schowe ◽  
Conner J. Langeberg ◽  
Namoos Siddique ◽  
Erich G. Chapman ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Conformational Changes ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
Spatial Constraints ◽  
Phase Synthesis ◽  
Naturally Occurring ◽  
Processive Enzyme ◽  
Moving Band ◽  
Hydrolysis Of

Understanding how oxidatively damaged RNA is handled intracellularly is of relevance due to the link between oxidized RNA and the progression/development of some diseases as well as aging. Among the ribonucleases responsible for the decay of modified (chemically or naturally) RNA is the exonuclease Xrn-1, a processive enzyme that catalyzes the hydrolysis of 5′-phosphorylated RNA in a 5′→3′ direction. We set out to explore the reactivity of this exonuclease towards oligonucleotides (ONs, 20-nt to 30-nt long) of RNA containing 8-oxo-7,8-dihydroguanosine (8-oxoG), obtained via solid-phase synthesis. The results show that Xrn-1 stalled at sites containing 8-oxoG, evidenced by the presence of a slower moving band (via electrophoretic analyses) than that observed for the canonical analogue. The observed fragment(s) were characterized via PAGE and MALDI-TOF to confirm that the oligonucleotide fragment(s) contained a 5′-phosphorylated 8-oxoG. Furthermore, the yields for this stalling varied from app. 5–30% with 8-oxoG located at different positions and in different sequences. To gain a better understanding of the decreased nuclease efficiency, we probed: 1) H-bonding and spatial constraints; 2) anti-syn conformational changes; 3) concentration of divalent cation; and 4) secondary structure. This was carried out by introducing methylated or brominated purines (m1G, m6,6A, or 8-BrG), probing varying [Mg2+], and using circular dichroism (CD) to explore the formation of structured RNA. It was determined that spatial constraints imposed by conformational changes around the glycosidic bond may be partially responsible for stalling, however, the results do not fully explain some of the observed higher stalling yields. We hypothesize that altered π-π stacking along with induced H-bonding interactions between 8-oxoG and residues within the binding site may also play a role in the decreased Xrn-1 efficiency. Overall, these observations suggest that other factors, yet to be discovered/established, are likely to contribute to the decay of oxidized RNA. In addition, Xrn-1 degraded RNA containing m1G, and stalled mildly at sites where it encountered m6,6A, or 8-BrG, which is of particular interest given that the former two are naturally occurring modifications.

Docking, Binding Free Energy Estimation, and MD Simulation of Newly Designed CQ and HCQ Analogues Against the Spike-ACE2 Complex of SARS-CoV-2

2021 ◽  
Vol 6 (4) ◽  
pp. 77-89
Author(s):  
Anjoomaara H. Patel ◽  
Riya B. Patel ◽  
MahammadHussain J. Memon ◽  
Samiya S. Patel ◽  
Sharav A. Desai ◽  
...  
Keyword(s):  
Free Energy ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Docking Studies ◽  
Radius Of Gyration ◽  
Ligand Interaction ◽  
Energy Estimation ◽  
Efficacious Treatment ◽  
Protein Ligand Interaction ◽  
Derivatives Of

The coronavirus disease 2019 (COVID-19) virus has been spreading rapidly, and scientists are endeavouring to discover drugs for its efficacious treatment. Chloroquine phosphate, an old drug for treatment of malaria, has shown to have apparent efficacy and acceptable safety against COVID-19. As a part of Drug Discovery Hackathon-2020, in this study, the authors have tried making the derivatives of CQ and HCQ using MarvinSketch by ChemAxon. Molecular docking studies of these ligands were performed using Glide by Schrodinger, and ADME profiles were obtained by using QikProp. The obtained results after data analysis demonstrated that ligands HCQ_imidazoll, choloroquine_3c, HCQ_pyrrolC had good binding affinity and complied with all the ADME parameters. The molecular dynamic simulation of these ligands in complex with the 2019-nCoV RBD/ACE-2-B0AT1 complex PDB ID: 6M17 were carried out, and the parameters like RMSD, RMSF, and radius of gyration were observed to understand the fluctuations and protein-ligand interaction.

2/3D-QSAR, molecular docking and MD simulation studies of FtsZ protein targeting benzimidazoles derivatives

2019 ◽  
Vol 78 ◽  
pp. 398-413 ◽  
Author(s):  
Shahzaib Ahamad ◽  
Asimul Islam ◽  
Faizan Ahmad ◽  
Neeraj Dwivedi ◽  
Md. Imtaiyaz Hassan
Keyword(s):  
Molecular Docking ◽  
Md Simulation ◽  
Protein Targeting ◽  
3D Qsar ◽  
Simulation Studies ◽  
Ftsz Protein

scholarly journals Coarse-Grained Models of RNA Nanotubes for Large Time Scale Studies in Biomedical Applications

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 195 ◽  
Author(s):  
Shyam Badu ◽  
Sanjay Prabhakar ◽  
Roderick Melnik
Keyword(s):  
Physical Properties ◽  
Time Scale ◽  
Biomedical Applications ◽  
Md Simulation ◽  
Large Time ◽  
Coarse Grained ◽  
Dihedral Angles ◽  
Computation Cost ◽  
In Series ◽  
Large Time Scale

In order to describe the physical properties of large time scale biological systems, coarse-grained models play an increasingly important role. In this paper we develop Coarse-Grained (CG) models for RNA nanotubes and then, by using Molecular Dynamics (MD) simulation, we study their physical properties. Our exemplifications include RNA nanotubes of 40 nm long, equivalent to 10 RNA nanorings connected in series. The developed methodology is based on a coarse-grained representation of RNA nanotubes, where each coarse bead represents a group of atoms. By decreasing computation cost, this allows us to make computations feasible for realistic structures of interest. In particular, for the developed coarse-grained models with three bead approximations, we calculate the histograms for the bond angles and the dihedral angles. From the dihedral angle histograms, we analyze the characteristics of the links used to build the nanotubes. Furthermore, we also calculate the bead distances along the chains of RNA strands in the nanoclusters. The variations in these features with the size of the nanotube are discussed in detail. Finally, we present the results on the calculation of the root mean square deviations for a developed RNA nanotube to demonstrate the equilibration of the systems for drug delivery and other biomedical applications such as medical imaging and tissue engineering.

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