Structural Insights into the IL12:IL12 Receptor Complex Assembly by Molecular Modeling, Docking, and Molecular Dynamics Simulation

2020 ◽  
Vol 23 ◽  
Author(s):  
Sakshi Singh ◽  
Geeta Rai
Keyword(s):  
Structure Prediction ◽  
Md Simulation ◽  
De Novo ◽  
3D Structure ◽  
Computational Method ◽  
Dynamics Simulation ◽  
Hematopoietic Progenitor Cell ◽  
Interleukin 12 ◽  
Type I ◽  
Progenitor Cell Proliferation

Background: Interleukin-12 receptor (IL12R) is a type I cytokine receptor that can promote hematopoiesis and regulate innate and adaptive immunity. It binds with the IL12 ligand, which activates the IL-12 signaling pathway that triggers hematopoietic progenitor cell proliferation and differentiation process. The structure of IL12:IL12R complex is not known. Objective: The present work describes a de novo computational method for rational protein designing to elucidate the structure of IL12:IL12R complex. Methods: Homology modeling, docking, and MD simulation methods were used to design mimics of the interaction of IL12 and IL12R. Results: 3D structure prediction and validation confirms the accurate structure of IL12R protein that contains immunoglobin domain, fibronectin type three domain, cytokine-binding domain, and WSXWS motif. Molecular docking and MD simulation revealed that IL12R bound tightly with IL12 ligand at their interface. The estimated binding energy of the docked complex was -26.7 kcal/mol, and the interface area was 281.4 Å2. Hotspot prediction suggested that ARG34, SER58, GLU61, CYS62, LEU63, SER73, ASP142, GLN146, LYS168, THR169 ARG181, ARG183, ARG189, and TYR193 residues in IL12 ligand interacted with SER175, ALA176, CYS177, PRO178, ALA179, ALA180, GLU181, GLU182, ALA192, VAL193, HIS194, ARG208, TYR246, GLN289, ASP290, ARG291, TYR292, TYR293 and SER294 residues in IL12 receptor. Conclusion: The results of the study provides a simulated molecular structure of IL12:IL12R complex that could offer a promising target complex to substantiate IL12 based drug-designing approaches.

scholarly journals Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency

2021 ◽  
Vol 6 (60) ◽  
pp. eabf9564
Author(s):  
Thomas Magg ◽  
Tsubasa Okano ◽  
Lars M. Koenig ◽  
Daniel F.R. Boehmer ◽  
Samantha L. Schwartz ◽  
...  
Keyword(s):  
B Cells ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Dynamics Simulation ◽  
Recurrent Fever ◽  
Type I ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Gain Of Function ◽  
Translational Arrest

Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon–induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2′-5′-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell–derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L–mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.

scholarly journals All-atom 3D structure prediction of transmembrane β-barrel proteins from sequences

2015 ◽  
Vol 112 (17) ◽  
pp. 5413-5418 ◽  
Author(s):  
Sikander Hayat ◽  
Chris Sander ◽  
Debora S. Marks ◽  
Arne Elofsson
Keyword(s):  
Structure Prediction ◽  
De Novo ◽  
3D Structure ◽  
3D Models ◽  
Sequence Information ◽  
Sequence Alignments ◽  
Residue Contacts ◽  
Machine Learning Approach ◽  
3D Structure Prediction ◽  
Structure Accuracy

Transmembrane β-barrels (TMBs) carry out major functions in substrate transport and protein biogenesis but experimental determination of their 3D structure is challenging. Encouraged by successful de novo 3D structure prediction of globular and α-helical membrane proteins from sequence alignments alone, we developed an approach to predict the 3D structure of TMBs. The approach combines the maximum-entropy evolutionary coupling method for predicting residue contacts (EVfold) with a machine-learning approach (boctopus2) for predicting β-strands in the barrel. In a blinded test for 19 TMB proteins of known structure that have a sufficient number of diverse homologous sequences available, this combined method (EVfold_bb) predicts hydrogen-bonded residue pairs between adjacent β-strands at an accuracy of ∼70%. This accuracy is sufficient for the generation of all-atom 3D models. In the transmembrane barrel region, the average 3D structure accuracy [template-modeling (TM) score] of top-ranked models is 0.54 (ranging from 0.36 to 0.85), with a higher (44%) number of residue pairs in correct strand–strand registration than in earlier methods (18%). Although the nonbarrel regions are predicted less accurately overall, the evolutionary couplings identify some highly constrained loop residues and, for FecA protein, the barrel including the structure of a plug domain can be accurately modeled (TM score = 0.68). Lower prediction accuracy tends to be associated with insufficient sequence information and we therefore expect increasing numbers of β-barrel families to become accessible to accurate 3D structure prediction as the number of available sequences increases.

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 De novo ssRNA Aptamers against the SARS-CoV-2 Main Protease: In Silico Design and Molecular Dynamics Simulation

2021 ◽  
Vol 22 (13) ◽  
pp. 6874
Author(s):  
Francesco Morena ◽  
Chiara Argentati ◽  
Ilaria Tortorella ◽  
Carla Emiliani ◽  
Sabata Martino
Keyword(s):  
De Novo ◽  
Binding Free Energy ◽  
3D Structure ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Therapeutic Drug ◽  
Energy Calculation ◽  
Potential Candidate ◽  
Initial Sequence ◽  
Main Protease

Herein, we have generated ssRNA aptamers to inhibit SARS-CoV-2 Mpro, a protease necessary for the SARS-CoV-2 coronavirus replication. Because there is no aptamer 3D structure currently available in the databanks for this protein, first, we modeled an ssRNA aptamer using an entropic fragment-based strategy. We refined the initial sequence and 3D structure by using two sequential approaches, consisting of an elitist genetic algorithm and an RNA inverse process. We identified three specific aptamers against SARS-CoV-2 Mpro, called MAptapro, MAptapro-IR1, and MAptapro-IR2, with similar 3D conformations and that fall in the dimerization region of the SARS-CoV-2 Mpro necessary for the enzymatic activity. Through the molecular dynamic simulation and binding free energy calculation, the interaction between the MAptapro-IR1 aptamer and the SARS-CoV-2 Mpro enzyme resulted in the strongest and the highest stable complex; therefore, the ssRNA MAptapro-IR1 aptamer was selected as the best potential candidate for the inhibition of SARS-CoV-2 Mpro and a perspective therapeutic drug for the COVID-19 disease.

PREDICTION OF THE EXPOSURE STATUS OF TRANSMEMBRANE BETA BARREL RESIDUES FROM PROTEIN SEQUENCE

2011 ◽  
Vol 09 (01) ◽  
pp. 43-65 ◽  
Author(s):  
SIKANDER HAYAT ◽  
PETER WALTER ◽  
YUNGKI PARK ◽  
VOLKHARD HELMS
Keyword(s):  
Structure Prediction ◽  
Prediction Accuracy ◽  
3D Structure ◽  
Chemical Properties ◽  
Confidence Score ◽  
Computational Method ◽  
Test Dataset ◽  
Hydrophobic Residues ◽  
Beta Barrel ◽  
Physico Chemical

We present BTMX (Beta barrel TransMembrane eXposure), a computational method to predict the exposure status (i.e. exposed to the bilayer or hidden in the protein structure) of transmembrane residues in transmembrane beta barrel proteins (TMBs). BTMX predicts the exposure status of known TM residues with an accuracy of 84.2% over 2,225 residues and provides a confidence score for all predictions. Predictions made are in concert with the fact that hydrophobic residues tend to be more exposed to the bilayer. The biological relevance of the input parameters is also discussed. The highest prediction accuracy is obtained when a sliding window comprising three residues with similar Cα - Cβ vector orientations is employed. The prediction accuracy of the BTMX method on a separate unseen non-redundant test dataset is 78.1%. By employing out-pointing residues that are exposed to the bilayer, we have identified various physico-chemical properties that show statistically significant differences between the beta strands located at the oligomeric interfaces compared to the non-oligomeric strands. The BTMX web server generates colored, annotated snake-plots as part of the prediction results and is available under the BTMX tab at . Exposure status prediction of TMB residues may be useful in 3D structure prediction of TMBs.

scholarly journals Probing the Structural Basis of Citrus Phytochrome B using Computational Modelling and Molecular Dynamics Simulation Approaches

2021 ◽  
Author(s):  
Muhammad Tahir ul Qamar ◽  
Muhammad Usman Mirza ◽  
Jia-Ming Song ◽  
Muhammad Junaid Rao ◽  
Xi-Tong Zhu ◽  
...  
Keyword(s):  
Md Simulation ◽  
Red Light ◽  
3D Structure ◽  
Computational Modelling ◽  
Structural Difference ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Functional Implications ◽  
Domain Organisation ◽  
Photosynthetic Potential

Phytochromes are known as red/far-red light photoreceptors and responsible for directing the photosensory responses across the species. Such responses majorly include photosynthetic potential and pigmentation in bacteria, whereas in a plant, they are involved in chloroplast development and photomorphogenesis. Many prokaryotic Phys have been modelled for their structural/functional analysis, but their plant counterparts have not been explored yet. To date, only the crystal structures of the photo-sensing module of PhyB isoform from Arabidopsis and Glycine have been resolved experimentally. Thus, in this study, we elucidated the complete 3D structure of Citrus PhyB. Initially, the structure and organisation of the Citrus PhyB have been predicted computationally, which were found to have the same domain organisation as A.thaliana and G.max PhyBs, yet their considerable distinct structural difference indicated potential divergence in signaling/functioning. Therefore, to evaluate the structural and functional implications of Citrus PhyB, we compared its structure with A. thaliana and G. max PhyBs using MD simulation. The modeling studies revealed that the region of Citrus PhyB-GAF domain possibly contributes to the variations. Hence, structural/molecular insights into Citrus PhyB can help to discover the Phys signaling and thus, an essential framework can be designed for optogenetic reagents and various agricultural benefits.

MODELING OF THREE DIMENSIONAL STRUCTURE OF HUMAN ALPHA-FETOPROTEIN COMPLEXED WITH DIETHYLSTILBESTROL: DOCKING AND MOLECULAR DYNAMICS SIMULATION STUDY

2012 ◽  
Vol 10 (02) ◽  
pp. 1241012 ◽  
Author(s):  
ALEXANDER A. TERENTIEV ◽  
NURBUBU T. MOLDOGAZIEVA ◽  
OLGA V. LEVTSOVA ◽  
DMITRY M. MAXIMENKO ◽  
DENIS A. BOROZDENKO ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Site ◽  
Simulation Study ◽  
Md Simulation ◽  
Hydrophobic Interactions ◽  
3D Structure ◽  
Three Dimensional ◽  
Alpha Fetoprotein ◽  
Dynamics Simulation ◽  
Dimensional Structure

It has been long experimentally demonstrated that human alpha-fetoprotein (HAFP) has an ability to bind immobilized estrogens with the most efficiency for synthetic estrogen analog — diethylstilbestrol (DES). However, the question remains why the human AFP (HAFP), unlike rodent AFP, cannot bind free estrogens. Moreover, despite the fact that AFP was first discovered more than 50 years ago and is presently recognized as a "golden standard" among onco-biomarkers, its three-dimensional (3D) structure has not been experimentally solved yet. In this work using MODELLER program, we generated 3D model of HAFP on the basis of homology with human serum albumin (HSA) and Vitamin D–binding protein (VTDB) with subsequent molecular docking of DES to the model structure and molecular dynamics (MD) simulation study of the complex obtained. The model constructed has U-shaped structure in which a cavity may be distinguished. In this cavity the putative estrogen-binding site is localized. Validation by RMSD calculation and with the use of PROCHECK program showed good quality of the model and stability of extended region of four alpha-helical structures that contains putative hormone-binding residues. Data extracted from MD simulation trajectory allow proposing two types of interactions between amino acid residues of HAFP and DES molecule: (1) hydrogen bonding with involvement of residues S445, R452, and E551; (2) hydrophobic interactions with participation of L138, M448, and M548 residues. A suggestion is made that immobilization of the hormone using a long spacer provides delivery of the estrogen molecule to the binding site and, thereby, facilitates interaction between HAFP and the hormone.

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