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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.


Structure of Erwinaze® predicted by MODELLER
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Fig1: Structure of Erwinaze® predicted by MODELLER

Mentions: The hypothetical model of Erwinaze® enzyme (Fig. 1) was validated using Rampage geometric evaluations to get Ramachandran plot. The plot has 97.2, 2.8 and 0.0 %of residues in favored, allowed and disallowed regions, respectively, and this strongly supports the geometric fitness of the modeled enzyme. Qmean6 score of 0.671, DFire energy of −455.15 and 84.326 % overall quality factors from ERRAT 2.0 indicates the good resolution structure. Secondary structure of the protein was also analyzed using PredictProtein tool (http://www.predictprotein.org). Protein was rich in loop region with a percentage of 46.01 residues and the remaining 29.14 and 24.85 % ones as helix and strands with two N-glycosylation sites in it. Along with these it also has eight sites for protein kinase C phosphorylation, three sites for Casein kinase II phosphorylation and one Tyrosine kinase phosphorylation. The final structure was further used to study the molecular interactions with ligand molecule.Fig. 1


Exploration of the binding modes of l -asparaginase complexed with its amino acid substrates by molecular docking, dynamics and simulation
Structure of Erwinaze® predicted by MODELLER
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Structure of Erwinaze® predicted by MODELLER
Mentions: The hypothetical model of Erwinaze® enzyme (Fig. 1) was validated using Rampage geometric evaluations to get Ramachandran plot. The plot has 97.2, 2.8 and 0.0 %of residues in favored, allowed and disallowed regions, respectively, and this strongly supports the geometric fitness of the modeled enzyme. Qmean6 score of 0.671, DFire energy of −455.15 and 84.326 % overall quality factors from ERRAT 2.0 indicates the good resolution structure. Secondary structure of the protein was also analyzed using PredictProtein tool (http://www.predictprotein.org). Protein was rich in loop region with a percentage of 46.01 residues and the remaining 29.14 and 24.85 % ones as helix and strands with two N-glycosylation sites in it. Along with these it also has eight sites for protein kinase C phosphorylation, three sites for Casein kinase II phosphorylation and one Tyrosine kinase phosphorylation. The final structure was further used to study the molecular interactions with ligand molecule.Fig. 1

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.