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

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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.


Rg plots for apo state enzyme, Erwinaze® + l-Asn and Erwinaze® + l-Gln complexes
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Fig6: Rg plots for apo state enzyme, Erwinaze® + l-Asn and Erwinaze® + l-Gln complexes

Mentions: Radius of gyration (Rg) was done to analyze the structural compactness of enzyme and was calculated using g_gyrate tool of GROMACS. Though the modeled enzyme in its free state has some structural compactness, bounded complexes were shown their fluctuating nature from Rg plots. Complex 1 has displayed the drifts during entire MD run in the array of 2.0 and 2.08 nm. In the plot of complex 2, it revealed its compactness with a little drift at 15 ns time point with the Rg values oscillating between 2.0 and 2.06 nm (Fig. 6).Fig. 6


Exploration of the binding modes of l -asparaginase complexed with its amino acid substrates by molecular docking, dynamics and simulation
Rg plots for apo state enzyme, Erwinaze® + l-Asn and Erwinaze® + l-Gln complexes
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: Rg plots for apo state enzyme, Erwinaze® + l-Asn and Erwinaze® + l-Gln complexes
Mentions: Radius of gyration (Rg) was done to analyze the structural compactness of enzyme and was calculated using g_gyrate tool of GROMACS. Though the modeled enzyme in its free state has some structural compactness, bounded complexes were shown their fluctuating nature from Rg plots. Complex 1 has displayed the drifts during entire MD run in the array of 2.0 and 2.08 nm. In the plot of complex 2, it revealed its compactness with a little drift at 15 ns time point with the Rg values oscillating between 2.0 and 2.06 nm (Fig. 6).Fig. 6

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.