Computational investigation of impact of Pb(II) and Ni(II) ions on hUNG enzyme: insights from molecular dynamics simulations.

Human uracil DNA glycosylase (hUNG), a crucial player in the initiation of the base excision repair pathway, is susceptible to alterations in function and conformation induced by the accumulation of toxic metals. Despite the recognized impact of toxic metals on DNA repair enzymes, there exists a notable deficiency in theoretical investigations addressing this phenomenon. This study investigates the impact of toxic heavy metal ions, Pb(II) and Ni(II), on the stability of hUNG through molecular dynamics (MD) simulations. The initial analysis involved the identification of key cavities in the hUNG enzyme. Notably, the active site cavity emerged as a promising site for ligand binding. Subsequently, AutoDockTools software was employed to dock Pb(II) and Ni(II) onto the identified cavities, followed by extensive MD simulations. The MD analysis, encompassing parameters such as root mean square deviation, radius of gyration, solvent accessible surface area, hydrogen bond variations, Ramachandran plot, principal component analysis, and root mean square fluctuations, collectively revealed distinct alterations in the behavior of the enzyme upon complexation with Pb(II) and Ni(II). Interestingly, the enzyme exhibited enhanced structural stability, reduced flexibility, and modified hydrogen bonding patterns in the presence of these toxic metal ions. The observed limitation in structural flexibility implies a more rigid and stable conformation when the enzyme complex with Pb(II) and Ni(II) compared to its free form. This structural alteration may lead to a potential reduction in enzymatic activity, suggesting that toxic metal ions influence the functional dynamics of hUNG. These computational findings offer valuable insights into the molecular interactions between metal ions and enzymes.