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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.


RMSF of Cα atoms for apo state enzyme, Erwinaze® + l-Asn and Erwinaze® + l-Gln complexes
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Fig5: RMSF of Cα atoms for apo state enzyme, Erwinaze® + l-Asn and Erwinaze® + l-Gln complexes

Mentions: In the analysis of g_rmsf results, many oscillations in the residues with Cα atoms were observed in case of first complex with a fall and amendment in initial peak due to the binding of l-Asn in that region. This substrate binding also influenced the entire enzyme with several numbers of residual fluctuations with a near RMSF value of 0.3 nm (Fig. 5). The same plot also disclosed the presence of a second high peak in the vicinity of bounded residues establishing H-bonds with ligand leading to a very high RMSF value of around 0.6 nm in complex 2, leaving most of the other residues stable. The comparison of RMSF outcomes exhibited minor variations in ligand binding sites (Table 3) and their effect on complex formation.Fig. 5


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

Fig5: RMSF of Cα atoms for apo state enzyme, Erwinaze® + l-Asn and Erwinaze® + l-Gln complexes
Mentions: In the analysis of g_rmsf results, many oscillations in the residues with Cα atoms were observed in case of first complex with a fall and amendment in initial peak due to the binding of l-Asn in that region. This substrate binding also influenced the entire enzyme with several numbers of residual fluctuations with a near RMSF value of 0.3 nm (Fig. 5). The same plot also disclosed the presence of a second high peak in the vicinity of bounded residues establishing H-bonds with ligand leading to a very high RMSF value of around 0.6 nm in complex 2, leaving most of the other residues stable. The comparison of RMSF outcomes exhibited minor variations in ligand binding sites (Table 3) and their effect on complex formation.Fig. 5

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.