Molecular dynamic simulations of Escherichia coli l-asparaginase to illuminate its role in deamination of asparagine and glutamine residues

Abstract

Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. l-Asparagine (l-Asn) and l-Glutamine (l-Gln) deamination play a crucial role in ALL treatment. Role of Elspar® (l-asparaginase from Escherichia coli) in regulation of l-Asn and l-Gln has been confirmed by the other researchers through experimental studies. Therapeutic research against ALL remained elusive with the lack of information on molecular interactions of Elspar® with amino acid substrates. In the present study, using different docking tools binding cavities, key residues in binding and ligand binding mechanisms were identified. For the apo state enzyme and ligand bound state complexes, MD simulations were performed. Trajectory analysis for 30 ns run confirmed the kinship of l-Asn with l-asparaginase enzyme in the dynamic system with less stability in comparison to l-Gln docked complex. Overall findings strongly supported the bi-functional nature of the enzyme drug. A good number of conformational changes were observed with 1NNS structure due to ligand binding. Results of present study give much more information on structural and functional aspects of E. coli l-asparaginase upon the interaction with its ligands which may be useful in designing effective therapeutics for ALL.Electronic supplementary materialThe online version of this article (doi:10.1007/s13205-015-0339-9) contains supplementary material, which is available to authorized users.

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“…This can be evidenced from the tables Table 1 and 2 that 28, 20 and 37% lower binding energies for L-asparagine for Lys43Ser, Ile70Leu and Ile101Val, respectively. Reddy et al, 10 and Oza et al, 15 reported similar trend of binding energies for both substrates with PDB ID: 1NNS and L-asparaginase of Withania sominefera respectively, however, these energy values are much lower compared to the selected model protein in the present study. This observation further confirms that selected mutant protein can be a promising candidate for ALL treatment.…”

“…Molecular dynamics simulations were carried out for independent wild-type protein as well as mutant Y306L using GROMACS 5.0.4 package along with GROMOS96 54a7 force field after solvation by simple point charge (SPC) keeping water model embedded in cubic simulation boxes with minimum edge distance of 10 Å. 10 The particle mesh Ewald method was used to treat long-range Coulomb interactions. During this, the bond lengths were constrained using the linear constraint solver (LINCS) algorithm.…”

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“…Radius of gyration (R g) of both ACE2 complexes describes overall spread of molecule during a 20 ns MD run. A low Rg value indicates better structural integrity and folding behavior (Erva et al, 2016). A slight increase in Rg value of the intact ACE2-RBD complex was observed during first 5 ns of the run, then after no further drifts till end ( Figure 5, red line), however, the tACE2-RBD complex was found stable throughout the MD run ( Figure 5, violet line), which indicates its structural integrity.…”

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