Molecular Modeling, Interacting Residues and other Structural Analyses for Human SOCS3, Gp130 and JAK Proteins: A Detailed Computational Approach for Proteins Involved in Feedback Inhibition

2021 ◽  
Vol 11 ◽  
Author(s):  
Arundhati Banerjee ◽  
Rakhi Dasgupta
Keyword(s):  
Feedback Inhibition ◽  
Solvent Accessibility ◽  
3D Structure ◽  
Protein Docking ◽  
Sh2 Domain ◽  
Dynamics Simulation ◽  
Signaling Cascade ◽  
Protein Kinase Activity ◽  
Stability Parameters ◽  
Socs3 Protein

Background: When STAT3 is activated only by the IL6 family of proteins, then gp130 (having a phosphopeptide motif) interacts with human SOCS3 which further binds to JAK and inhibits its protein kinase activity. Interaction of gp130 with SOCS3 targets only the IL-6 signaling cascade. The interaction occurs when SOCS3 binds to a particular motif on gp130 (centered upon pTyr759) after its phosphorylation. Previously, wet laboratory studies were done but computational exploration for the participating residues remained unexplored. Methodology: The 3D structure of human SOCS3 protein was modeled and its stereo-chemical parameters were satisfied. Crystallographic structures of gp130-phosphopeptide and JAK were studied. After protein docking, the complex underwent minimization and molecular dynamics simulation. Different stability parameters and binding patterns with residues were evaluated Results, Discussion and Conclusion: The best modeled structure of SOCS3 protein was selected and found that it had three helices and seven sheets interspersed with coils. Arg133, Tyr137 and Tyr98 from SOCS3 formed manifold binding patterns with gp130 (mainly with pTyr759 and Glu758). Lys62, Lys63 and Arg65 from SOCS3 were also found to interact with Val762 of gp130. Interactions with JAK were also studied. Residue 53, 62-65, 98, 133, 136 and 137 formed the predominant binding pockets in SOCS3. They can serve as important target sites as well. Altogether, it created elctrostatically charged pockets to accommodate the partner proteins for each other. Gp130 phosphopeptide was observed to be tightly accommodated in the electrostatically positive zones on SOCS3 surface. Net area for solvent accessibility was also found to get drastically reduced implying high participation of residues. Earlier studies documented that the interaction of these three proteins occurs with affinity and have satisfactory association with each other. Here in this study, free energy of binding for the triple protein interaction through the ΔG values helped to infer that SOCS3 interacted spontaneously (in thermodynamic sense). Many helical conformations formed coiled-coils providing high flexibility to interact spontaneously. Most of the interactions were through the responsible SH2 domain (46-127 residue length) of SOCS3. Residues 53, 62-64 and 98 formed coils while the residue number 137adopted sheet conformation from coils. Future Scope: This study shall instigate to block the gp130-binding sites of SOCS3 through targeting of drugs, thereby preventing SOCS3-gp130 interaction. This would allow JAK-STAT signaling cascade which is paramount for several biological functions

Proteomic Analysis of Medicinal Plant Calotropis Gigantea by insilico Peptide Mass Fingerprinting

2020 ◽  
Vol 16 ◽  
Author(s):  
Saad Ur Rehman ◽  
Muhammad Rizwan ◽  
Sajid Khan ◽  
Azhar Mehmood ◽  
Anum Munir
Keyword(s):  
Medicinal Plant ◽  
Structure Prediction ◽  
3D Structure ◽  
Peptide Mass Fingerprinting ◽  
Protein Docking ◽  
Receptor Protein ◽  
Human Leukemia ◽  
Protein Database ◽  
Calotropis Gigantea ◽  
Peptide Mass

: Medicinal plants are the basic source of medicinal compounds traditionally used for the treatment of human diseases. Calotropis gigantea a medicinal plant belonging to the family of Apocynaceae in the plant kingdom and subfamily Asclepiadaceae usually bearing multiple medicinal properties to cure a variety of diseases. Background: The Peptide Mass Fingerprinting (PMF) identifies the proteins from a reference protein database by comparing the amino acid sequence that is previously stored in a database and identified. Method: The calculation of insilico peptide masses is done through the ExPASy PeptideMass and these masses are used to identify the peptides from MASCOT online server. Anticancer probability is calculated from the iACP server, docking of active peptides is done by CABS-dock the server. Objective: The purpose of the study is to identify the peptides having anti-cancerous properties by in-silico peptide mass fingerprinting. Results : The anti-cancerous peptides are identified with the MASCOT peptide mass fingerprinting server, the identified peptides are screened and only the anti-cancer are selected. De novo peptide structure prediction is used for 3D structure prediction by PEP-FOLD 3 server. The docking results confirm strong bonding with the interacting amino acids of the receptor protein of breast cancer BRCA1 which shows the best peptide binding to the Active chain, the human leukemia protein docking with peptides shows the accurate binding. Conclusion : These peptides are stable and functional and are the best way for the treatment of cancer and many other deadly diseases.

scholarly journals Modeling and Molecular Dynamics of the 3D Structure of the HPV16 E7 Protein and Its Variants

2021 ◽  
Vol 22 (3) ◽  
pp. 1400
Author(s):  
Ciresthel Bello-Rios ◽  
Sarita Montaño ◽  
Olga Lilia Garibay-Cerdenares ◽  
Lilian Esmeralda Araujo-Arcos ◽  
Marco Antonio Leyva-Vázquez ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
3D Structure ◽  
Epidemiological Studies ◽  
Dynamics Simulation ◽  
Structural Refinement ◽  
Oncogenic Potential ◽  
Structural Differences ◽  
Reference Protein ◽  
E6 And E7 ◽  
First Time

The oncogenic potential of high-risk human papillomavirus (HPV) is predicated on the production of the E6 and E7 oncoproteins, which are responsible for disrupting the control of the cell cycle. Epidemiological studies have proposed that the presence of the N29S and H51N variants of the HPV16 E7 protein is significantly associated with cervical cancer. It has been suggested that changes in the amino acid sequence of E7 variants may affect the oncoprotein 3D structure; however, this remains uncertain. An analysis of the structural differences of the HPV16 E7 protein and its variants (N29S and H51N) was performed through homology modeling and structural refinement by molecular dynamics simulation. We propose, for the first time, a 3D structure of the E7 reference protein and two of Its variants (N29S and H51N), and conclude that the mutations induced by the variants in N29S and H51N have a significant influence on the 3D structure of the E7 protein of HPV16, which could be related to the oncogenic capacity of this protein.

scholarly journals Identification and Characterization of a Novel Thermostable and Salt-Tolerant β-1,3 Xylanase from Flammeovirga pacifica Strain WPAGA1

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1287
Author(s):  
Zhiwei Yi ◽  
Zhengwen Cai ◽  
Bo Zeng ◽  
Runying Zeng ◽  
Guangya Zhang
Keyword(s):  
Thermal Stability ◽  
Salt Tolerance ◽  
3D Structure ◽  
Catalytic Efficiency ◽  
Dynamics Simulation ◽  
Carbohydrate Binding ◽  
Salt Tolerant ◽  
Excellent Thermal Stability ◽  
Moderately Thermophilic

β-1,3 xylanase is an important enzyme in the biorefinery process for some algae. The discovery and characterization of new β-1,3 xylanase is a hot research topic. In this paper, a novel β-1,3 xylanase (Xyl88) is revealed from the annotated genome of Flammeovirga pacifica strain WPAGA1. Bioinformatic analysis shows that Xyl88 belongs to the glycoside hydrolase 26 (GH26) with a suspected CBM (carbohydrate-binding module) sequence. The activity of rXyl88 is 75% of the highest enzyme activity (1.5 mol/L NaCl) in 3 mol/L NaCl buffer, which suggests good salt tolerance of rXy188. The optimum reaction temperature in the buffer without NaCl and with 1.5 mol/L NaCl is 45 °C and 55 °C, respectively. Notably, the catalytic efficiency of rXyl88 (kcat/Km) is approximately 20 higher than that of the thermophilic β-1,3 xylanase that has the highest catalytic efficiency. Xyl88 in this study becomes the most efficient enzyme ever found, and it is also the first reported moderately thermophilic and salt-tolerant β-1,3 xylanase. Results of molecular dynamics simulation further prove the excellent thermal stability of Xyl88. Moreover, according to the predicted 3D structure of the Xyl88, the surface of the enzyme is distributed with more negative charges, which is related to its salt tolerance, and significantly more hydrogen bonds and Van der Waals force between the intramolecular residues, which is related to its thermal stability.

scholarly journals Electrostatics of Tau Protein by Molecular Dynamics

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 116 ◽  
Author(s):  
Tarsila Castro ◽  
Florentina-Daniela Munteanu ◽  
Artur Cavaco-Paulo
Keyword(s):  
Molecular Dynamics ◽  
3D Structure ◽  
Three Dimensional ◽  
Dynamics Simulation ◽  
Microtubule Assembly ◽  
Interaction Sites ◽  
Disordered Protein ◽  
Fluid Environment ◽  
Function Relationship ◽  
Insight Into

Tau is a microtubule-associated protein that promotes microtubule assembly and stability. This protein is implicated in several neurodegenerative diseases, including Alzheimer’s. To date, the three-dimensional (3D) structure of tau has not been fully solved, experimentally. Even the most recent information is sometimes controversial in regard to how this protein folds, interacts, and behaves. Predicting the tau structure and its profile sheds light on the knowledge about its properties and biological function, such as the binding to microtubules (MT) and, for instance, the effect on ionic conductivity. Our findings on the tau structure suggest a disordered protein, with discrete portions of well-defined secondary structure, mostly at the microtubule binding region. In addition, the first molecular dynamics simulation of full-length tau along with an MT section was performed, unveiling tau structure when associated with MT and interaction sites. Electrostatics and conductivity were also examined to understand how tau affects the ions in the intracellular fluid environment. Our results bring a new insight into tau and tubulin MT proteins, their characteristics, and the structure–function relationship.

P3DOCK: a protein–RNA docking webserver based on template-based and template-free docking

2019 ◽  
Vol 36 (1) ◽  
pp. 96-103 ◽  
Author(s):  
Jinfang Zheng ◽  
Xu Hong ◽  
Juan Xie ◽  
Xiaoxue Tong ◽  
Shiyong Liu
Keyword(s):  
Success Rate ◽  
Clustering Algorithm ◽  
Hybrid Methods ◽  
3D Structure ◽  
Three Dimensional ◽  
Protein Docking ◽  
Ease Of Use ◽  
Supplementary Information ◽  
Main Function ◽  
Rna Interaction

AbstractMotivationThe main function of protein–RNA interaction is to regulate the expression of genes. Therefore, studying protein–RNA interactions is of great significance. The information of three-dimensional (3D) structures reveals that atomic interactions are particularly important. The calculation method for modeling a 3D structure of a complex mainly includes two strategies: free docking and template-based docking. These two methods are complementary in protein–protein docking. Therefore, integrating these two methods may improve the prediction accuracy.ResultsIn this article, we compare the difference between the free docking and the template-based algorithm. Then we show the complementarity of these two methods. Based on the analysis of the calculation results, the transition point is confirmed and used to integrate two docking algorithms to develop P3DOCK. P3DOCK holds the advantages of both algorithms. The results of the three docking benchmarks show that P3DOCK is better than those two non-hybrid docking algorithms. The success rate of P3DOCK is also higher (3–20%) than state-of-the-art hybrid and non-hybrid methods. Finally, the hierarchical clustering algorithm is utilized to cluster the P3DOCK’s decoys. The clustering algorithm improves the success rate of P3DOCK. For ease of use, we provide a P3DOCK webserver, which can be accessed at www.rnabinding.com/P3DOCK/P3DOCK.html. An integrated protein–RNA docking benchmark can be downloaded from http://rnabinding.com/P3DOCK/benchmark.html.Availability and implementationwww.rnabinding.com/P3DOCK/P3DOCK.html.Supplementary informationSupplementary data are available at Bioinformatics online.

scholarly journals Detailed Analysis of 17β-Estradiol-Aptamer InteractionsAptamer Interactions: A Molecular Dynamics Simulation Study

2018 ◽  
Author(s):  
Alexander Eisold ◽  
Dirk Labudde
Keyword(s):  
Md Simulation ◽  
3D Structure ◽  
Dynamics Simulation ◽  
Coarse Grained ◽  
Negative Effects ◽  
Time Step ◽  
Binding Characteristics ◽  
Structure Information ◽  
Potential Binding ◽  
Interior Loop

Micro-pollutants such as 17β-Estradiol (E2) have been detected in different water resources and their negative effects on the environment and organisms have been observed. Aptamers are established as a possible detection tool, but the underlying ligand binding is largely unexplored. In this study, a previously described 35-mer E2-specific aptamer was used to analyse the binding characteristics between E2 and the aptamer with a MD simulation in an aqueous medium. Because there is no 3D structure information available for this aptamer, it was modeled using coarse-grained modeling method. The E2 ligand was positioned inside a potential binding area of the predicted aptamer structure, the complex was used for an 25 ns MD simulation, and the interactions were examined for each time step. We identified E2-specific bases within the interior loop of the aptamer and also demonstrated the influence of frequently underestimated water-mediated hydrogen bonds. The study contributes to the understanding of the behavior of ligands binding with aptamer structure in an aqueous solution. The developed workflow allows generating and examining further appealing ligand-aptamer complexes.

scholarly journals Insights in the Interaction of HPV-16 E6 and Its Variants (E-G350, E-A176/G350, E-C188/G350, AAa and AAc) with MAGI-1

2021 ◽  
Author(s):  
Lilian Esmeralda Araujo- Arcos ◽  
Ciresthel Bello-Rios ◽  
Olga Lilia Garibay- Cerdenares ◽  
Marco Antonio Leyva-Vázquez ◽  
Sarita Montaño ◽  
...  
Keyword(s):  
Cellular Protein ◽  
Protein Docking ◽  
Dynamics Simulation ◽  
Scaffolding Protein ◽  
Binding Motif ◽  
Pdz Domains ◽  
Guanylate Kinase ◽  
Hpv 16 ◽  
E6 Gene ◽  
Oncogenic Protein

Oncogenic protein E6 from Human Papilloma Virus 16 (HPV-16) mediates the degradation of Membrane-associated guanylate kinase with inverted domain structure-1 (MAGI-1), throughout the interaction of its protein binding motif (PBM) with the Discs-large homologous regions 1 (PDZ1) domain of MAG1-1. Generic variation in the E6 gene that translates to changes in the protein’s amino acidic sequence modifies the interaction of E6 with the cellular protein MAGI-1. MAGI-1 is a scaffolding protein found at tight junctions of epithelial cells, where it interacts with a variety of proteins regulating signaling pathways. MAGI-1 is a multidomain protein containing two WW (rsp-domain-9), one guanylate kinase-like, and six PDZ domains. PDZ domains played an important role in the function of MAGI-1 and served as targets for several viral proteins including the HPV-16 E6. The aim of this work was to evaluate, with an in silico approach, employing molecular dynamics simulation and protein-protein docking, the interaction of the intragenic variants E-G350 (L83V), E-C188/G350 (E29Q/L83V), E-A176/G350 (D25N/L83V), E6-AAa (Q14H/H78Y/83V) y E6-AAc (Q14H/I27RH78Y/L83V) and E6-reference of HPV-16 with MAGI-1. We found that variants E-G350, E-C188/G350, E-A176/G350, AAa and AAc increase their affinity to our two models of MAGI-1 compared to E6-reference.

scholarly journals Pinostrobin suppresses the Ca2+-signal-dependent growth arrest in yeast by inhibiting the Swe1-mediated G2 cell-cycle regulation

2020 ◽  
Vol 20 (4) ◽  
Author(s):  
Jumpol Sopanaporn ◽  
Sirinporn Suksawatamnuay ◽  
Amanulia Sardikin ◽  
Rittirat Lengwittaya ◽  
Warinthorn Chavasiri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Regulatory Protein ◽  
Inhibitory Effect ◽  
Genetically Engineered ◽  
Flavonoid Compound ◽  
Signaling Cascade ◽  
Protein Kinase Activity ◽  
G2 Phase

ABSTRACT Pinostrobin, a flavonoid compound known for its diverse pharmacological actions, including anti-leukemic and anti-inflammatory activities, has been repeatedly isolated by various screenings, but its action mechanism is still obscure. Previously, pinostrobin was rediscovered in our laboratory using a yeast-based assay procedure devised specifically for the inhibitory effect on the activated Ca2+ signaling that leads the cells to severe growth retardation in the G2 phase. Here, we attempted to identify target of pinostrobin employing the genetic techniques available in the yeast. Using various genetically engineered yeast strains in which the Ca2+-signaling cascade can be activated by the controlled expression of the various signaling molecules of the cascade, its target was narrowed down to Swe1, the cell-cycle regulatory protein kinase. The Swe1 kinase is situated at the downstream of the Ca2+-signaling cascade and downregulates the Cdc28/Clb complex by phosphorylating the Cdc28 moiety of the complex in the G2 phase. We further demonstrated that pinostrobin inhibits the protein kinase activity of Swe1 in vivo as estimated by the decreased level of Cdc28 phosphorylation at Tyr-19. Since the yeast SWE1 gene is an ortholog for the human WEE1 gene, our finding implied a potentiality of pinostrobin as the G2 checkpoint abrogator in cancer chemotherapy.

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