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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.


Inter-hydrogen bonding for docked complexes a Erwinaze¬ģ¬†+¬†l-Asn, b Erwinaze¬ģ¬†+¬†l-Gln
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Fig7: Inter-hydrogen bonding for docked complexes a Erwinaze¬ģ¬†+¬†l-Asn, b Erwinaze¬ģ¬†+¬†l-Gln

Mentions: To authenticate the hydrogen bonding pattern docking results, H-bond analysis was also executed along with the intact MD trajectories (Fig. 7). Surprisingly, the desired stable H-bonding pattern for complex 1 described missing linkage of hydrogen bonds between receptor and ligand. During 7.5 ns point the H-bonds were increased to 5, but after 4.03 ns h-bonds were missed and again formed from 6 ns. The same was again repeated at around 9 ns and 11 ns time points. Finally, after 12.6 ns there were no h-bonds, showing the disappearance of H-bond linkage between enzyme and substrate (Fig. 7a). The loss of intermolecular hydrogen bands may induce a spatial conformational change in the tertiary structure of the enzyme i.e., unstable structure of docked complex. This becomes a major shortcoming for the enzyme in therapeutic perspective, supporting possibility of its lower effect on cancer cells. On the other hand, it has shown the constant H-bond pattern with l-Gln throughout MD run with an average of 7 H-bonds throughout entire trajectory (Fig. 7b). H-bond pattern of both complexes did not draw a parallel with the docking result and this gives scope for the further investigation for efficient and firm drug in ALL therapy. Entire computational analysis describes the necessity of further intensive investigation on other sources of l-Asparaginase enzyme which is more effective on cancerous cells with fewer side effects.Fig. 7


Exploration of the binding modes of l -asparaginase complexed with its amino acid substrates by molecular docking, dynamics and simulation
Inter-hydrogen bonding for docked complexes a Erwinaze¬ģ¬†+¬†l-Asn, b Erwinaze¬ģ¬†+¬†l-Gln
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig7: Inter-hydrogen bonding for docked complexes a Erwinaze¬ģ¬†+¬†l-Asn, b Erwinaze¬ģ¬†+¬†l-Gln
Mentions: To authenticate the hydrogen bonding pattern docking results, H-bond analysis was also executed along with the intact MD trajectories (Fig. 7). Surprisingly, the desired stable H-bonding pattern for complex 1 described missing linkage of hydrogen bonds between receptor and ligand. During 7.5 ns point the H-bonds were increased to 5, but after 4.03 ns h-bonds were missed and again formed from 6 ns. The same was again repeated at around 9 ns and 11 ns time points. Finally, after 12.6 ns there were no h-bonds, showing the disappearance of H-bond linkage between enzyme and substrate (Fig. 7a). The loss of intermolecular hydrogen bands may induce a spatial conformational change in the tertiary structure of the enzyme i.e., unstable structure of docked complex. This becomes a major shortcoming for the enzyme in therapeutic perspective, supporting possibility of its lower effect on cancer cells. On the other hand, it has shown the constant H-bond pattern with l-Gln throughout MD run with an average of 7 H-bonds throughout entire trajectory (Fig. 7b). H-bond pattern of both complexes did not draw a parallel with the docking result and this gives scope for the further investigation for efficient and firm drug in ALL therapy. Entire computational analysis describes the necessity of further intensive investigation on other sources of l-Asparaginase enzyme which is more effective on cancerous cells with fewer side effects.Fig. 7

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.