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Exploration of the binding modes of l -asparaginase complexed with its amino acid substrates by molecular docking, dynamics and simulation

View Article: PubMed Central - PubMed

ABSTRACT

Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. l-Asparagine (l-Asn) and l-glutamine (l-Gln) deamination plays crucial role in ALL treatment. Role of Erwinaze® (l-asparaginase from Erwinia chrysanthemi) in regulation of l-Asn and l-Gln has been confirmed by the experimental studies. Therapeutic research against ALL remained elusive with the lack of structural information on Erwinaze® enzyme. In this present study, homology model of the Erwinaze® was developed using MODELLER and the same was validated by various quality indexing tools. For the apo state enzyme and ligand bound state complexes molecular dynamics (MD) simulation was performed. The trajectory analysis showed the confirmational changes of structures in the dynamic system. Ligand binding mechanisms were studied using different docking tools to interpret the various ligand-receptor interactions and binding free energies. MD simulation of docked complex with l-Gln ligand substrate showed the defined structural folding with stable conformation over the l-Asn complex in dynamic environment. This research reports give much more information on structural and functional aspects of Erwinaze® with its ligands which may be useful in designing of effective therapeutics for ALL.

Electronic supplementary material: The online version of this article (doi:10.1007/s13205-016-0422-x) contains supplementary material, which is available to authorized users.

No MeSH data available.


Total energy of Erwinaze® apo enzyme after molecular dynamics and simulations
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Fig3: Total energy of Erwinaze® apo enzyme after molecular dynamics and simulations

Mentions: To check the structural behavior of modeled enzyme and docked complexes in the dynamic system MD simulations were performed and the trajectory analysis was done using GROMACS utilities. The total energy found from g_energy results for Erwinaze® modeled enzyme was found to be −9,30,919 kJ/mol demonstrating that the model was energetically stable (Fig. 3). The structural convergence includes terms like root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg) and hydrogen bond (H-bond) analysis. In the g_rms based results with backbone atoms (Fig. 4), apo state enzyme is stable right from the launch of MD run with a drift at 10 ns followed by a stable confirmation till the finale of entire run.Fig. 3


Exploration of the binding modes of l -asparaginase complexed with its amino acid substrates by molecular docking, dynamics and simulation
Total energy of Erwinaze® apo enzyme after molecular dynamics and simulations
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835421&req=5

Fig3: Total energy of Erwinaze® apo enzyme after molecular dynamics and simulations
Mentions: To check the structural behavior of modeled enzyme and docked complexes in the dynamic system MD simulations were performed and the trajectory analysis was done using GROMACS utilities. The total energy found from g_energy results for Erwinaze® modeled enzyme was found to be −9,30,919 kJ/mol demonstrating that the model was energetically stable (Fig. 3). The structural convergence includes terms like root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg) and hydrogen bond (H-bond) analysis. In the g_rms based results with backbone atoms (Fig. 4), apo state enzyme is stable right from the launch of MD run with a drift at 10 ns followed by a stable confirmation till the finale of entire run.Fig. 3

View Article: PubMed Central - PubMed

ABSTRACT

Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. l-Asparagine (l-Asn) and l-glutamine (l-Gln) deamination plays crucial role in ALL treatment. Role of Erwinaze® (l-asparaginase from Erwinia chrysanthemi) in regulation of l-Asn and l-Gln has been confirmed by the experimental studies. Therapeutic research against ALL remained elusive with the lack of structural information on Erwinaze® enzyme. In this present study, homology model of the Erwinaze® was developed using MODELLER and the same was validated by various quality indexing tools. For the apo state enzyme and ligand bound state complexes molecular dynamics (MD) simulation was performed. The trajectory analysis showed the confirmational changes of structures in the dynamic system. Ligand binding mechanisms were studied using different docking tools to interpret the various ligand-receptor interactions and binding free energies. MD simulation of docked complex with l-Gln ligand substrate showed the defined structural folding with stable conformation over the l-Asn complex in dynamic environment. This research reports give much more information on structural and functional aspects of Erwinaze® with its ligands which may be useful in designing of effective therapeutics for ALL.

Electronic supplementary material: The online version of this article (doi:10.1007/s13205-016-0422-x) contains supplementary material, which is available to authorized users.

No MeSH data available.