scholarly journals Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer nsp16/nsp10 Bound to the Cofactor SAM

2020 ◽  
Vol 7 ◽  
Author(s):  
Md Fulbabu Sk ◽  
Nisha Amarnath Jonniya ◽  
Rajarshi Roy ◽  
Sayan Poddar ◽  
Parimal Kar
Keyword(s):  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Conformational Dynamics ◽  
Rna Stability ◽  
Protein Translation ◽  
Vital Role ◽  
Potential Target ◽  
Mtase Activity ◽  
Computational Alanine Scanning ◽  
Novel Coronavirus

Recently, a highly contagious novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has emerged, posing a global threat to public health. Identifying a potential target and developing vaccines or antiviral drugs is an urgent demand in the absence of approved therapeutic agents. The 5′-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability and protein translation in the virus. SARS-CoV-2 encodes S-adenosyl-L-methionine (SAM) dependent methyltransferase (MTase) enzyme characterized by nsp16 (2′-O-MTase) for generating the capped structure. The present study highlights the binding mechanism of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, we investigated the conformational dynamics and energetics behind the binding of SAM to nsp16 and nsp16/nsp10 heterodimer by employing molecular dynamics simulations in conjunction with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method. We observed from our simulations that the presence of nsp10 increases the favorable van der Waals and electrostatic interactions between SAM and nsp16. Thus, nsp10 acts as a stimulator for the strong binding of SAM to nsp16. The hydrophobic interactions were predominately identified for the nsp16-nsp10 interactions. Also, the stable hydrogen bonds between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) play a vital role in the dimerization of nsp16 and nsp10. Besides, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Hence, the dimer interface of nsp16/nsp10 could also be a potential target in retarding the 2′-O-MTase activity in SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.

scholarly journals Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer Nsp16/nsp10 Bound to the Cofactor SAM

2020 ◽  
Author(s):  
Md Fulbabu Sk ◽  
Nisha Amarnath Jonniya ◽  
Rajarshi Roy ◽  
Sayan Poddar ◽  
Parimal Kar
Keyword(s):  
Protein Interactions ◽  
Electrostatic Interactions ◽  
Immune Escape ◽  
Hydrophobic Interactions ◽  
Conformational Dynamics ◽  
Rna Stability ◽  
Protein Translation ◽  
Dynamics Simulation ◽  
Mtase Activity ◽  
Computational Alanine Scanning

Recently, a highly contagious novel coronavirus (COVID-19 or SARS-CoV-2) has emerged as a global threat in people's health and global economies. Identification of the potential targets and development of a vaccine or antiviral drugs is an urgent demand. The 5’-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability, protein translation, and for viral immune escape. SARSCoV encodes S-adenosyl-L-methionine dependent (SAM) methyltransferase (MTase) enzyme characterized by nsp16 (2’-O-MTase) for generating the capped structure. The present article highlights the binding mechanisms of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, the conformational dynamics and energetic behind the SAM binding to nsp16 in its monomer and dimer form was analyzed by using an extensive molecular dynamics simulation along with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA). Our results show that the presence of nsp10 increases the favorable van der Waal and electrostatic interactions between the SAM and nsp16, thus nsp10 acts as a stimulator for its strong binding. The interaction profile suggests that hydrophobic interactions were predominately identified for protein-protein interactions. Also, the stable hydrogen bond between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) plays a vital role in the nsp16-nsp10 interface. Further, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Therefore, the dimer interface of nsp16/nsp10 could also be a potential target to suppress the 2’-O-MTase activity of SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding of nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.

scholarly journals Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer Nsp16/nsp10 Bound to the Cofactor SAM

2020 ◽  
Author(s):  
Md Fulbabu Sk ◽  
Nisha Amarnath Jonniya ◽  
Rajarshi Roy ◽  
Sayan Poddar ◽  
Parimal Kar
Keyword(s):  
Protein Interactions ◽  
Electrostatic Interactions ◽  
Immune Escape ◽  
Hydrophobic Interactions ◽  
Conformational Dynamics ◽  
Rna Stability ◽  
Protein Translation ◽  
Dynamics Simulation ◽  
Mtase Activity ◽  
Computational Alanine Scanning

Recently, a highly contagious novel coronavirus (COVID-19 or SARS-CoV-2) has emerged as a global threat in people's health and global economies. Identification of the potential targets and development of a vaccine or antiviral drugs is an urgent demand. The 5’-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability, protein translation, and for viral immune escape. SARSCoV encodes S-adenosyl-L-methionine dependent (SAM) methyltransferase (MTase) enzyme characterized by nsp16 (2’-O-MTase) for generating the capped structure. The present article highlights the binding mechanisms of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, the conformational dynamics and energetic behind the SAM binding to nsp16 in its monomer and dimer form was analyzed by using an extensive molecular dynamics simulation along with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA). Our results show that the presence of nsp10 increases the favorable van der Waal and electrostatic interactions between the SAM and nsp16, thus nsp10 acts as a stimulator for its strong binding. The interaction profile suggests that hydrophobic interactions were predominately identified for protein-protein interactions. Also, the stable hydrogen bond between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) plays a vital role in the nsp16-nsp10 interface. Further, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Therefore, the dimer interface of nsp16/nsp10 could also be a potential target to suppress the 2’-O-MTase activity of SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding of nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.

scholarly journals NSP16 2′-O-MTase in Coronavirus Pathogenesis: Possible Prevention and Treatments Strategies

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 538
Author(s):  
Li-Jen Chang ◽  
Tsung-Hsien Chen
Keyword(s):  
Nonstructural Protein ◽  
Treatment Strategies ◽  
Vital Role ◽  
Upper Respiratory Tract ◽  
Mtase Activity ◽  
Life Threatening ◽  
End Capping ◽  
Human Coronaviruses ◽  
Novel Coronavirus ◽  
Tract Infections

Several life-threatening viruses have recently appeared, including the coronavirus, infecting a variety of human and animal hosts and causing a range of diseases like human upper respiratory tract infections. They not only cause serious human and animal deaths, but also cause serious public health problems worldwide. Currently, seven species are known to infect humans, namely SARS-CoV-2, MERS-CoV, SARS-CoV, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1. The coronavirus nonstructural protein 16 (NSP16) structure is similar to the 5′-end capping system of mRNA used by eukaryotic hosts and plays a vital role in evading host immunity response and protects the nascent viral mRNA from degradation. NSP16 is also well-conserved among related coronaviruses and requires its binding partner NSP10 to activate its enzymatic activity. With the continued threat of viral emergence highlighted by human coronaviruses and SARS-CoV-2, mutant strains continue to appear, affecting the highly conserved NSP16: this provides a possible therapeutic approach applicable to any novel coronavirus. To this end, current information on the 2′-O-MTase activity mechanism, the differences between NSP16 and NSP10 in human coronaviruses, and the current potential prevention and treatment strategies related to NSP16 are summarized in this review.

scholarly journals Inhibitory effects of aviptadil on the SARS-CoV-2 nsp10/ nsp16 protein complex

2021 ◽  
Author(s):  
Sultan F. Alnomasy ◽  
Bader S. Alotaibi ◽  
Ziyad M. Aldosari ◽  
Ahmed H. Mujamammi ◽  
Pragya Anand ◽  
...  
Keyword(s):  
Human Lung ◽  
Rna Stability ◽  
Protein Translation ◽  
Inhibitory Effect ◽  
Lung Epithelial Cells ◽  
Immune Recognition ◽  
Inhibitory Effects ◽  
Mtase Activity ◽  
Lung Epithelial ◽  
Initial Binding

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in late 2019, causes COVID-19, a disease that has been spreading rapidly worldwide. In human lung epithelial cells and monocytes, RLF-100 (aviptadil) has been found to inhibit the RNA replication machinery of SARS-CoV-2, which includes several non-structural proteins (nsp) that play essential roles in synthesizing and replicating viral RNA. This virus is unique in requiring nsp10 and nsp16 for methyltransferase (MTase) activity. This enzyme is essential for RNA stability, protein translation, and viral ability to escape the host's immune recognition. Therefore, we aimed to use bioinformatics tools to analyze aviptadil's inhibitory effect on the SARS-CoV-2 nsp10/nsp16 complex. We present a comprehensive, in silico-generated picture showing how aviptadil may interact with the nsp complex. Specifically, our model predicts how the initial binding of aviptadil to nsp10 and nsp16 may occur. This knowledge can assist drug development efforts against SARS-CoV-2 by providing more target information against nsp16.

Novel Coronavirus SARS-CoV-2 (COVID-19) and Pregnancy: A hypothetical view

2020 ◽  
Vol 20 ◽  
Author(s):  
Ahmed RG
Keyword(s):  
Immune System ◽  
Cellular Therapy ◽  
Early Stage ◽  
Control Strategies ◽  
Vital Role ◽  
Healthy Life ◽  
Global Pandemic ◽  
Maternal Immune System ◽  
Perinatal Management ◽  
Novel Coronavirus

Background: The complications of the SARS-CoV-2 infection and its COVID-19 disease on mothers and their offspring are less known. Objective: The aim of this review was to determine the transmission, severity, complications of SARS-CoV-2 infection during the pregnancy. This review showed the influence of COVID-19 disease on the neonatal neurogenesis. Owing to no specific vaccines or medicines that were reported for the treatment of COVID-19 disease, this review suggested some control strategies like treatments (medicinal plants, antiviral therapy, cellular therapy, and immunotherapy), nutrition uptake, prevention, and recommendations. Discussion: This overview showed in severely states that SARS-CoV-2 infection during the early stage of pregnancy might increase the risk of stress, panic, and anxiety. This disorder can disturb the maternal immune system, and thus causing a neurodevelopmental disturbance. This hypothesis may be depending on the severity and intensity of the SARS-CoV-2 infection during pregnancy. However, vertical transmission of SARS-CoV-2 from dams to their fetuses is absent until now. Conclusion: During this global pandemic disease, maintaining safety during pregnancy, vaginal delivery, and breastfeeding may play a vital role in a healthy life for the offspring. Thus, international and national corporations should be continuing for perinatal management, particularly during the next pandemic or disaster time.

scholarly journals Characterization of Virus Adsorption by Using DEAE-Sepharose and Octyl-Sepharose

2002 ◽  
Vol 68 (8) ◽  
pp. 3965-3968 ◽  
Author(s):  
Patricia A. Shields ◽  
Samuel R. Farrah
Keyword(s):  
Sodium Chloride ◽  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Chloride Concentration ◽  
Sodium Chloride Concentration ◽  
Virus Adsorption ◽  
Nacl Concentration

ABSTRACT Viruses were characterized by their adsorption to DEAE-Sepharose or by their elution from octyl-Sepharose by using buffered solutions of sodium chloride with different ionic strengths. Viruses whose adsorption to DEAE-Sepharose was reduced most rapidly by an increase in the sodium chloride concentration were considered to have the weakest electrostatic interactions with the solids; these viruses included MS2, E1, and φX174. Viruses whose adsorption to DEAE-Sepharose was reduced least rapidly were considered to have the strongest electrostatic interactions with the column; these viruses included P1, T4, T2, and E5. All of the viruses studied adsorbed to octyl-Sepharose in the presence of 4 M NaCl. Viruses that were eluted most rapidly following a decrease in the concentration of NaCl were considered to have the weakest hydrophobic interactions with the column; these viruses included φX174, CB4, and E1. Viruses that were eluted least rapidly from the columns after the NaCl concentration was decreased were considered to have the strongest hydrophobic interactions with the column; these viruses included f2, MS2, and E5.

scholarly journals Protein-Based Nanohydrogels for Bioactive Delivery

2021 ◽  
Vol 9 ◽  
Author(s):  
Subhash Chander ◽  
Giriraj T. Kulkarni ◽  
Neerupma Dhiman ◽  
Harsha Kharkwal
Keyword(s):  
Drug Delivery ◽  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Biological Fluids ◽  
Three Dimensional ◽  
Covalent Bond ◽  
Ionic Concentration ◽  
Covalent Bonds ◽  
Encapsulation Process ◽  
Insightful Analysis

Hydrogels possess a unique three-dimensional, cross-linked network of polymers capable of absorbing large amounts of water and biological fluids without dissolving. Nanohydrogels (NGs) or nanogels are composed of diverse types of polymers of synthetic or natural origin. Their combination is bound by a chemical covalent bond or is physically cross-linked with non-covalent bonds like electrostatic interactions, hydrophobic interactions, and hydrogen bonding. Its remarkable ability to absorb water or other fluids is mainly attributed to hydrophilic groups like hydroxyl, amide, and sulphate, etc. Natural biomolecules such as protein- or peptide-based nanohydrogels are an important category of hydrogels which possess high biocompatibility and metabolic degradability. The preparation of protein nanohydrogels and the subsequent encapsulation process generally involve use of environment friendly solvents and can be fabricated using different proteins, such as fibroins, albumin, collagen, elastin, gelatin, and lipoprotein, etc. involving emulsion, electrospray, and desolvation methods to name a few. Nanohydrogels are excellent biomaterials with broad applications in the areas of regenerative medicine, tissue engineering, and drug delivery due to certain advantages like biodegradability, biocompatibility, tunable mechanical strength, molecular binding abilities, and customizable responses to certain stimuli like ionic concentration, pH, and temperature. The present review aims to provide an insightful analysis of protein/peptide nanohydrogels including their preparation, biophysiochemical aspects, and applications in diverse disciplines like in drug delivery, immunotherapy, intracellular delivery, nutraceutical delivery, cell adhesion, and wound dressing. Naturally occurring structural proteins that are being explored in protein nanohydrogels, along with their unique properties, are also discussed briefly. Further, the review also covers the advantages, limitations, overview of clinical potential, toxicity aspects, stability issues, and future perspectives of protein nanohydrogels.

scholarly journals Bone Morphogenetic Protein 2 (BMP-2) Aggregates Can be Solubilized by Albumin—Investigation of BMP-2 Aggregation by Light Scattering and Electrophoresis

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1143
Author(s):  
Julius Sundermann ◽  
Holger Zagst ◽  
Judith Kuntsche ◽  
Hermann Wätzig ◽  
Heike Bunjes
Keyword(s):  
Light Scattering ◽  
Bone Morphogenetic Protein ◽  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Pharmaceutical Research ◽  
Bone Morphogenetic Protein 2 ◽  
Growth Factor Delivery ◽  
Surface Charges ◽  
High Tendency ◽  
Morphogenetic Protein

Bone morphogenetic protein 2 (BMP-2) has a high tendency to aggregate at physiological pH and physiological ionic strength, which can complicate the development of growth factor delivery systems. The aggregation behavior in differently concentrated BMP-2 solutions was investigated using dynamic and static light scattering. It was found that at higher concentrations larger aggregates are formed, whose size decreases again with increasing dilution. A solubilizing effect and therefore less aggregation was observed upon the addition of albumin. Imaged capillary isoelectric focusing and the simulation of the surface charges of BMP-2 were used to find a possible explanation for the unusually low solubility of BMP-2 at physiological pH. In addition to hydrophobic interactions, attractive electrostatic interactions might be decisive in the aggregation of BMP-2 due to the particular distribution of surface charges. These results help to better understand the solubility behavior of BMP-2 and thus support future pharmaceutical research and the development of new strategies for the augmentation of bone healing.

scholarly journals Structural insight into human N6amt1–Trm112 complex functioning as a protein methyltransferase

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Wenjing Li ◽  
Yu Shi ◽  
Tianlong Zhang ◽  
Jie Ye ◽  
Jianping Ding
Keyword(s):  
Epigenetic Modification ◽  
Substrate Binding ◽  
Hydrophobic Surface ◽  
Vital Role ◽  
Biochemical Data ◽  
Modification System ◽  
Restriction Modification System ◽  
Mtase Activity ◽  
Protein Methyltransferase ◽  
Bona Fide

Abstract DNA methylation is an important epigenetic modification in many organisms and can occur on cytosine or adenine. N6-methyladenine (6mA) exists widespreadly in bacterial genomes, which plays a vital role in the bacterial restriction-modification system. Recently, 6mA has also been reported to exist in the genomes of a variety of eukaryotes from unicellular organisms to metazoans. There were controversial reports on whether human N6amt1, which was originally reported as a glutamine MTase for eRF1, is a putative 6mA DNA MTase. We report here the crystal structure of human N6amt1–Trm112 in complex with cofactor SAM. Structural analysis shows that Trm112 binds to a hydrophobic surface of N6amt1 to stabilize its structure but does not directly contribute to substrate binding and catalysis. The active site and potential substrate-binding site of N6amt1 are dominantly negatively charged and thus are unsuitable for DNA binding. The biochemical data confirm that the complex cannot bind DNA and has no MTase activity for DNA, but exhibits activity for the methylation of Gln185 of eRF1. Our structural and biochemical data together demonstrate that N6amt1 is a bona fide protein MTase rather than a DNA MTase.

scholarly journals RNA-binding protein 39: a promising therapeutic target for cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Caipeng Xu ◽  
Xiaohua Chen ◽  
Xuetian Zhang ◽  
Dapeng Zhao ◽  
Zhihui Dou ◽  
...  
Keyword(s):  
Clinical Application ◽  
Rna Binding ◽  
Drug Research ◽  
Protein Translation ◽  
Vital Role ◽  
Binding Motif ◽  
Promising Therapeutic Target ◽  
Key Factor ◽  
Mrna And Protein Expression ◽  
Development Prospects

AbstractRNA-binding motif protein 39 (RBM39), as a key factor in tumor-targeted mRNA and protein expression, not only plays a vital role in tumorigenesis, but also has broad development prospects in clinical treatment and drug research. Moreover, since RBM39 was identified as a target of sulfonamides, it has played a key role in the emerging field of molecule drug development. Hence, it is of great significance to study the interaction between RBM39 and tumors and the clinical application of drug-targeted therapy. In this paper, we describe the possible multi-level regulation of RBM39, including gene transcription, protein translation, and alternative splicing. Importantly, the molecular function of RBM39 as an important splicing factor in most common tumors is systematically outlined. Furthermore, we briefly introduce RBM39’s tumor-targeted drug research and its clinical application, hoping to give reference significance for the molecular mechanism of RBM39 in tumors, and provide reliable ideas for in-depth research for future therapeutic strategies.

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