L-asparaginase (L-ASN) is an anti-cancer enzyme therapeutic drug that exerts cytotoxicity via inhibition of protein synthesis through depletion of L-asparagine in the tumor microenvironment. The therapeutic performance of the native drug is partial due to the associated instability, reduced half-life and immunogenic complications.In this study, we attempted the modification of recombinant L-asparaginase with PEG and an integrated computational strategy to probe the PEGylation in the protein to understand the biological stability/activity imparted by PEG.In vitro PEGylation of recombinant L-ASN was carried out and further evaluated in silico.PEGylation enhanced thermal and pH activities with extended serum half-life and resistance to proteases compared to the native enzyme. The molecular dynamics analysis revealed intricate interactions required in the coupling of PEG to L-asparaginase to bestow stronger binding affinity of L-asparagine moiety towards L-asparaginase. PEG-asparagine complex ensured stable conformation over both the native protein and asparagine-protein complex thus elucidating the PEG-induced stable conformation in the protein. PEG mechanistically stabilized L-asparaginase through inducing pocket modification at the receptor to adapt to the cavity.The study provides the rationale of PEGylation in imparting the stability towards Lasparaginase which would expand the potential application of L-asparaginase enzyme for the effective treatment of cancer.
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