Abstract:
Mutations in DNA occur due to exposure to chemicals, toxins, and radiation. The presence of
uracil in DNA is a modification that occurs due to the misincorporation and spontaneous
deamination of cytosine. Glycosylases can repair mutated DNA, and human uracil DNA
glycosylase (hUNG) is one such DNA repair enzyme that initiates the base excision repair
pathway. However, the activity of these enzymes gets affected when exposed to toxic metals.
Therefore, it is essential to study the mechanism of action of the toxic metals with these
enzymes. Experimental investigations have revealed that Cd(II) ions can inhibit the activity of
hUNG. These studies suggest that the inhibition takes place due to the replacement of the
catalytic water molecule found in the active site of the enzyme by the Cd(II) ion. Other than
Cd(II) ion, As(III) is also considered a toxic metal ion categorized under human carcinogens.
Therefore, the work here has focused on the accumulation of As(III) with the hUNG enzyme,
and the intension of this work was to study the effect of As(III) ion on hUNG. The study was
done using CavityPlus web server and computational analysis based on molecular dynamic
(MD) simulations considering two systems of the enzyme; in the presence and absence of the
As(III) ion. The CavityPlus web server results showed that the number of cavities of the
enzyme changes for the two situations of the enzyme. Further, the ability of a ligand to bind
with a cavity of the hUNG was comparatively studied using the ligandability results obtained
from the server. The root means square deviation and total energy analysis done using the
simulation trajectories showed that the enzyme and the system with As(III) obtain high stability
compared to the free enzyme and the system, respectively. The localization of the residues of
the enzyme in the Ramachandran plot showed that a high percent of residues of the enzyme
with As(III) lie in the favorable region of the plot. Based on the analysis of these results, it is
concluded that As(III) ion can reduce the activity of the enzyme by forming a stable enzymemetal ion system.
