scholarly journals The Construction of Chimeric T-Cell Receptor with Spacer Base of Modeling Study of VHH and MUC1 Interaction

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Nazanin Pirooznia ◽  
Sadegh Hasannia ◽  
Majid Taghdir ◽  
Fatemeh Rahbarizadeh ◽  
Morteza Eskandani
Keyword(s):  
Root Mean Square ◽  
Conformational Changes ◽  
Cell Receptor ◽  
Dynamics Simulation ◽  
Specific Response ◽  
Conformational Structure ◽  
Mean Square ◽  
Chimeric Receptors ◽  
Cell Immunotherapy ◽  
And Function

Adaptive cell immunotherapy with the use of chimeric receptors leads to the best and most specific response against tumors. Chimeric receptors consist of a signaling fragment, extracellular spacer, costimulating domain, and an antibody. Antibodies cause immunogenicity; therefore, VHH is a good replacement for ScFv in chimeric receptors. Since peptide sequences have an influence on chimeric receptors, the effect of peptide domains on each other's conformation were investigated. CD3Zeta, CD28, VHH and CD8α, and FcgIIα are used as signaling moieties, costimulating domain, antibody, and spacers, respectively. To investigate the influence of the ligation of spacers on the conformational structure of VHH, models of VHH were constructed. Molecular dynamics simulation was run to study the influence of the presence of spacers on the conformational changes in the binding sites of VHH. Root mean square deviation and root mean square fluctuation of critical segments in the binding site showed no noticeable differences with those in the native VHH. Results from molecular docking revealed that the presence of spacer FcgIIα causes an increasing effect on VHH with MUC1 interaction. Each of the constructs was transformed into the Jurkat E6.1. Expression analysis and evaluation of their functions were examined. The results showed good expression and function.

scholarly journals Understanding the Effect of Structural Diversity in WRKY Transcription Factors on DNA Binding Efficiency through Molecular Dynamics Simulation

Biology ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 83
Author(s):  
Akshay Singh ◽  
Ajay Kumar Sharma ◽  
Nagendra Kumar Singh ◽  
Humira Sonah ◽  
Rupesh Deshmukh ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Dna Binding ◽  
Root Mean Square ◽  
Conformational Changes ◽  
Higher Plants ◽  
Crop Improvement ◽  
Dynamics Simulation ◽  
Type I ◽  
Mean Square ◽  
Different Types

A precise understanding of the molecular mechanism involved in stress conditions has great importance for crop improvement. Biomolecules, such as WRKY proteins, which are the largest transcription factor family that is widely distributed in higher plants, plays a significant role in plant defense response against various biotic and abiotic stressors. In the present study, an extensive homology-based three-dimensional model construction and subsequent interaction study of WRKY DNA-binding domain (DBD) in CcWRKY1 (Type I), CcWRKY51 (Type II), and CcWRKY70 (Type III) belonging to pigeonpea, a highly tolerant crop species, was performed. Evaluation of the generated protein models was done to check their reliability and accuracy based on the quantitative and qualitative parameters. The final model was subjected to investigate the comparative binding analysis of different types of WRKY–DBD with DNA-W-box (a cis-acting element) by protein–DNA docking and molecular dynamics (MD) simulation. The DNA binding specificity with WRKY variants was scrutinized through protein–DNA interaction using the HADDOCK server. The stability, as well as conformational changes of protein–DNA complex, was investigated through molecular dynamics (MD) simulations for 100 ns using GROMACS. Additionally, the comparative stability and dynamic behavior of each residue of the WRKY–DBD type were analyzed in terms of root mean square deviation (RMSD), root mean square fluctuation (RMSF)values of the backbone atoms for each frame taking the minimized structure as a reference. The details of DNA binding activity of three different types of WRKY–DBD provided here will be helpful to better understand the regulation of WRKY gene family members in plants.

scholarly journals Identification of Phosphatidylinositol 3-kinase δ (PI3Kδ) Inhibitor: Pharmacophore-based Virtual Screening and Molecular Dynamics Simulation

2020 ◽  
Vol 20 (5) ◽  
pp. 1070
Author(s):  
Muhammad Arba ◽  
Malindo Sufriadin ◽  
Daryono Hadi Tjahjono
Keyword(s):  
Molecular Dynamics ◽  
Root Mean Square ◽  
Conformational Changes ◽  
Binding Free Energy ◽  
Pharmacophore Model ◽  
Dynamics Simulation ◽  
Mean Square ◽  
Phosphatidylinositol 3 Kinase ◽  
Pharmacophore Modelling ◽  
Phosphatidylinositol 3

Phosphatidylinositol 3-kinase δ (PI3Kδ) is a validated drug target for the treatment of cancer. The present study aims to search for new inhibitors of PI3Kδ by employing pharmacophore modelling using LigandScout Advanced 4.3 software. The three hydrogen bond acceptors and two hydrophobic features were proposed as a pharmacophore model using LASW1976 structure. The model was then validated using the Area Under Curve (AUC) of Receiver Operating Characteristic (ROC) and GH score. It was used to screen new molecules in the ZINC database, which resulted in 599 hits. All 599 hits were then docked into PI3Kδ protein, and five best hits were submitted to 50 ns molecular dynamics simulations. Each hit complexed with PI3Kδ underwent minor conformational changes as indicated by the values of Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF). Furthermore, prediction of the binding free energy using Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) method showed that five hits, i.e., Lig25/ZINC253496376, Lig682/ZINC98047241, Lig449/ZINC85878047, Lig554/ZINC253389510, and Lig199/ZINC12638303, had lower binding energy compared to LASW1976. This result indicated their potentials as new inhibitors of PI3Kδ.

scholarly journals Structural flexibility and protein adaptation to temperature: Molecular dynamics analysis of malate dehydrogenases of marine molluscs

2018 ◽  
Vol 115 (6) ◽  
pp. 1274-1279 ◽  
Author(s):  
Yun-wei Dong ◽  
Ming-ling Liao ◽  
Xian-liang Meng ◽  
George N. Somero
Keyword(s):  
Molecular Dynamics ◽  
Root Mean Square ◽  
Temperature Effects ◽  
Significant Negative Correlation ◽  
Dynamics Simulation ◽  
Heat Denaturation ◽  
Structural Flexibility ◽  
Mean Square ◽  
Marine Molluscs ◽  
And Function

Orthologous proteins of species adapted to different temperatures exhibit differences in stability and function that are interpreted to reflect adaptive variation in structural “flexibility.” However, quantifying flexibility and comparing flexibility across proteins has remained a challenge. To address this issue, we examined temperature effects on cytosolic malate dehydrogenase (cMDH) orthologs from differently thermally adapted congeners of five genera of marine molluscs whose field body temperatures span a range of ∼60 °C. We describe consistent patterns of convergent evolution in adaptation of function [temperature effects on KM of cofactor (NADH)] and structural stability (rate of heat denaturation of activity). To determine how these differences depend on flexibilities of overall structure and of regions known to be important in binding and catalysis, we performed molecular dynamics simulation (MDS) analyses. MDS analyses revealed a significant negative correlation between adaptation temperature and heat-induced increase of backbone atom movements [root mean square deviation (rmsd) of main-chain atoms]. Root mean square fluctuations (RMSFs) of movement by individual amino acid residues varied across the sequence in a qualitatively similar pattern among orthologs. Regions of sequence involved in ligand binding and catalysis—termed mobile regions 1 and 2 (MR1 and MR2), respectively—showed the largest values for RMSF. Heat-induced changes in RMSF values across the sequence and, importantly, in MR1 and MR2 were greatest in cold-adapted species. MDS methods are shown to provide powerful tools for examining adaptation of enzymes by providing a quantitative index of protein flexibility and identifying sequence regions where adaptive change in flexibility occurs.

scholarly journals Effects of the Temperature and the pH on the Main Protease of SARS-CoV-2: A Molecular Dynamics Simulation Study

2021 ◽  
Vol 12 (6) ◽  
pp. 7239-7248
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Root Mean Square ◽  
Dynamics Simulation ◽  
Effect Of Temperature ◽  
Water Molecules ◽  
Mean Square ◽  
Main Protease ◽  
Decreasing Ph ◽  
Increasing Temperature

The novel coronavirus, recognized as COVID-19, is the cause of an infection outbreak in December 2019. The effect of temperature and pH changes on the main protease of SARS-CoV-2 were investigated using all-atom molecular dynamics simulation. The obtained results from the root mean square deviation (RMSD) and root mean square fluctuations (RMSF) analyses showed that at a constant temperature of 25℃ and pH=5, the conformational change of the main protease is more significant than that of pH=6 and 7. Also, by increasing temperature from 25℃ to 55℃ at constant pH=7, a remarkable change in protein structure was observed. The radial probability of water molecules around the main protease was decreased by increasing temperature and decreasing pH. The weakening of the binding energy between the main protease and water molecules due to the increasing temperature and decreasing pH has reduced the number of hydrogen bonds between the main protease and water molecules. Finding conditions that alter the conformation of the main protease could be fundamental because this change could affect the virus’s functionality and its ability to impose illness.

scholarly journals Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4829
Author(s):  
Sajjad Haider ◽  
Assem Barakat ◽  
Zaheer Ul-Haq
Keyword(s):  
Virtual Screening ◽  
Molecular Dynamic ◽  
Root Mean Square ◽  
Cancer Metastasis ◽  
Pharmacophore Model ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Dynamic Simulations

CXCL12 are small pro-inflammatory chemo-attractant cytokines that bind to a specific receptor CXCR4 with a role in angiogenesis, tumor progression, metastasis, and cell survival. Globally, cancer metastasis is a major cause of morbidity and mortality. In this study, we targeted CXCL12 rather than the chemokine receptor (CXCR4) because most of the drugs failed in clinical trials due to unmanageable toxicities. Until now, no FDA approved medication has been available against CXCL12. Therefore, we aimed to find new inhibitors for CXCL12 through virtual screening followed by molecular dynamics simulation. For virtual screening, active compounds against CXCL12 were taken as potent inhibitors and utilized in the generation of a pharmacophore model, followed by validation against different datasets. Ligand based virtual screening was performed on the ChEMBL and in-house databases, which resulted in successive elimination through the steps of pharmacophore-based and score-based screenings, and finally, sixteen compounds of various interactions with significant crucial amino acid residues were selected as virtual hits. Furthermore, the binding mode of these compounds were refined through molecular dynamic simulations. Moreover, the stability of protein complexes, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and radius of gyration were analyzed, which led to the identification of three potent inhibitors of CXCL12 that may be pursued in the drug discovery process against cancer metastasis.

scholarly journals Molecular Dynamics Simulation of Barnase: Contribution of Noncovalent Intramolecular Interaction to Thermostability

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Zhiguo Chen ◽  
Yi Fu ◽  
Wenbo Xu ◽  
Ming Li
Keyword(s):  
Molecular Dynamics ◽  
Thermal Stability ◽  
Molecular Dynamics Simulation ◽  
Root Mean Square ◽  
Clinical Medicine ◽  
Intramolecular Interaction ◽  
Salt Bridge ◽  
Dynamics Simulation ◽  
Mean Square ◽  
Thermal Stability Of

Bacillus amyloliquefaciensribonuclease Barnase (RNase Ba) is a 12 kD (kilodalton) small extracellular ribonuclease. It has broad application prospects in agriculture, clinical medicine, pharmaceutical, and so forth. In this work, the thermal stability of Barnase has been studied using molecular dynamics simulation at different temperatures. The present study focuses on the contribution of noncovalent intramolecular interaction to protein stability and how they affect the thermal stability of the enzyme. Profiles of root mean square deviation and root mean square fluctuation identify thermostable and thermosensitive regions of Barnase. Analyses of trajectories in terms of secondary structure content, intramolecular hydrogen bonds and salt bridge interactions indicate distinct differences in different temperature simulations. In the simulations, Four three-member salt bridge networks (Asp8-Arg110-Asp12, Arg83-Asp75-Arg87, Lys66-Asp93-Arg69, and Asp54-Lys27-Glu73) have been identified as critical salt bridges for thermostability which are maintained stably at higher temperature enhancing stability of three hydrophobic cores. The study may help enlighten our knowledge of protein structural properties, noncovalent interactions which can stabilize secondary peptide structures or promote folding, and also help understand their actions better. Such an understanding is required for designing efficient enzymes with characteristics for particular applications at desired working temperatures.

scholarly journals Screening of Potent Phytochemical Inhibitors Against SARS-CoV-2 Main Protease: An Integrative Computational Approach

2021 ◽  
Vol 1 ◽  
Author(s):  
Shafi Mahmud ◽  
Md. Robiul Hasan ◽  
Suvro Biswas ◽  
Gobindo Kumar Paul ◽  
Shamima Afrose ◽  
...  
Keyword(s):  
Root Mean Square ◽  
Global Economy ◽  
Transmission Rate ◽  
Accessible Surface Area ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Protease Inhibition ◽  
Main Protease

Coronavirus disease 2019 (COVID-19) is a potentially lethal and devastating disease that has quickly become a public health threat worldwide. Due to its high transmission rate, many countries were forced to implement lockdown protocols, wreaking havoc on the global economy and the medical crisis. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus for COVID-19, represent an effective target for the development of a new drug/vaccine because it is well-conserved and plays a vital role in viral replication. Mpro inhibition can stop the replication, transcription as well as recombination of SARS-CoV-2 after the infection and thus can halt the formation of virus particles, making Mpro a viable therapeutic target. Here, we constructed a phytochemical dataset based on a rigorous literature review and explored the probability that various phytochemicals will bind with the main protease using a molecular docking approach. The top three hit compounds, medicagol, faradiol, and flavanthrin, had binding scores of −8.3, −8.6, and −8.8 kcal/mol, respectively, in the docking analysis. These three compounds bind to the active groove, consisting of His41, Cys45, Met165, Met49, Gln189, Thr24, and Thr190, resulting in main protease inhibition. Moreover, the multiple descriptors from the molecular dynamics simulation, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, radius of gyration, and hydrogen bond analysis, confirmed the stable nature of the docked complexes. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis confirmed a lack of toxicity or carcinogenicity for the screened compounds. Our computational analysis may contribute toward the design of an effective drug against the main protease of SARS-CoV-2.

scholarly journals Use of multiple picosecond high-mass molecular dynamics simulations to predict crystallographic B-factors of folded globular proteins

2016 ◽  
Author(s):  
Yuan-Ping Pang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Molecular Dynamics Simulations ◽  
Root Mean Square ◽  
A Priori ◽  
Model Systems ◽  
Dynamics Simulation ◽  
High Mass ◽  
Mean Square ◽  
Dynamics Simulations

ABSTRACTPredicting crystallographic B-factors of a protein from a conventional molecular dynamics simulation is challenging in part because the B-factors calculated through sampling the atomic positional fluctuations in a picosecond molecular dynamics simulation are unreliable and the sampling of a longer simulation yields overly large root mean square deviations between calculated and experimental B-factors. This article reports improved B-factor prediction achieved by sampling the atomic positional fluctuations in multiple picosecond molecular dynamics simulations that use uniformly increased atomic masses by 100-fold to increase time resolution. Using the third immunoglobulin-binding domain of protein G, bovine pancreatic trypsin inhibitor, ubiquitin, and lysozyme as model systems, the B-factor root mean square deviations (mean ± standard error) of these proteins were 3.1 ± 0.2–9 ± 1 Å2for Cα and 7.3 ± 0.9–9.6 ± 0.2 Å2for Cγ, when the sampling was done, for each of these proteins, over 20 distinct, independent, and 50-picosecond high-mass molecular dynamics simulations using AMBER forcefield FF12MC or FF14SB. These results suggest that sampling the atomic positional fluctuations in multiple picosecond high-mass molecular dynamics simulations may be conducive toa prioriprediction of crystallographic B-factors of a folded globular protein.

scholarly journals The THE ROLE OF ASTAXANTHIN COMPARED WITH METFORMIN IN PREVENTING GLYCATED HUMAN SERUM ALBUMIN FROM POSSIBLE UNFOLDING: A MOLECULAR DYNAMIC STUDY

2019 ◽  
pp. 276-282
Author(s):  
SYAHPUTRA WIBOWO ◽  
SRI WIDYARTI ◽  
AKHMAD SABARUDIN ◽  
DJOKO WAHONO SOEATMADJI ◽  
SUTIMAN BAMBANG SUMITRO
Keyword(s):  
Diabetes Mellitus ◽  
Human Serum Albumin ◽  
Serum Albumin ◽  
Human Serum ◽  
Root Mean Square ◽  
Conformational Changes ◽  
Glycated Albumin ◽  
Mean Square ◽  
Discovery Studio ◽  
Significant Difference

Objectives: Albumin in diabetes mellitus undergoes conformational changes that affect the ability as an endogenous scavenger. Treatment with astaxanthin (ASX) expected to improve the function of albumin in case of diabetes mellitus. The objectives of this study are to compare the capability of ASX and metformin to prevent conformational changes on glycated albumin. Methods: Data mining is performed to obtain human serum albumin (HSA) (4K2C), glucose (79025), ASX (5281224), and metformin (4091). Data preparation used PyRx and Discovery Studio 2016 Client. PyRx is utilized for docking and analysis of receptor-ligand interactions with LigPlus and Discovery Studio 2016 Client. YASARA is used for molecular dynamics simulations with a running time of 15.000 ps. Results: A description of the glycated-HSA (gHSA) conformational changes that are bound to metformin has been successfully carried out. Changes that occur were unfolding and release of bonds in gHSA. Unfolding on gHSA includes the release of bonds between sites A and B. The root mean square deviation (RMSD) backbone value of metformin-gHSA shows a significant difference with gHSA at 8650 ps where gHSA showed 6.47 nm while the metformin-gHSA was 8.06 nm and continues to increase up to 15.72 nm at the end of the simulation. RMSD and root mean square fluctuation residues of gHSA which were interacted with ASX showed conditions close to normal HSA. In 11725 ps ASX-gHSA remained stable at 5.78 nm, whereas gHSA increased to 8.13 nm. gHSA at the end of the simulation showed a number of 9.052 nm while the normal HSA was 7.561 nm. Conclusion: This result indicated that ASX prevents gHSA from possible unfolding.

scholarly journals Luteolin and abyssinone II as potential inhibitors of SARS-CoV-2: an in silico molecular modeling approach in battling the COVID-19 outbreak

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Mohammad Mahfuz Ali Khan Shawan ◽  
Sajal Kumar Halder ◽  
Md. Ashraful Hasan
Keyword(s):  
Molecular Dynamics ◽  
Root Mean Square ◽  
In Silico ◽  
Binding Free Energy ◽  
Biologically Active ◽  
Dynamics Simulation ◽  
Mean Square ◽  
Efficient Treatment ◽  
Target Proteins

Abstract Background At present, the entire world is in a war against COVID-19 pandemic which has gradually led us toward a more compromised “new normal” life. SARS-CoV-2, the pathogenic microorganism liable for the recent COVID-19 outbreak, is extremely contagious in nature resulting in an unusual number of infections and death globally. The lack of clinically proven therapeutic intervention for COVID-19 has dragged the world’s healthcare system into the biggest challenge. Therefore, development of an efficient treatment scheme is now in great demand. Screening of different biologically active plant-based natural compounds could be a useful strategy for combating this pandemic. In the present research, a collection of 43 flavonoids of 7 different classes with previously recorded antiviral activity was evaluated via computational and bioinformatics tools for their impeding capacity against SARS-CoV-2. In silico drug likeness, pharmacophore and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile analysis of the finest ligands were carried out using DataWarrior, DruLiTo and admetSAR programs, respectively. Molecular docking was executed by AutoDock Vina, while molecular dynamics simulation of the target protein–ligand bound complexes was done using nanoscalable molecular dynamics and visual molecular dynamics software package. Finally, the molecular target analysis of the selected ligands within Homo sapiens was conducted with SwissTargetPredcition web server. Results Out of the forty-three flavonoids, luteolin and abyssinone II were found to develop successful docked complex within the binding sites of target proteins in terms of lowest binding free energy and inhibition constant. The root mean square deviation and root mean square fluctuation values of the docked complex displayed stable interaction and efficient binding between the ligands and target proteins. Both of the flavonoids were found to be safe for human use and possessed good drug likeness properties and target accuracy. Conclusions Conclusively, the current study proposes that luteolin and abyssinone II might act as potential therapeutic candidates for SARS-CoV-2 infection. In vivo and in vitro experiments, however, should be taken under consideration to determine the efficiency and to demonstrate the mechanism of action.

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