Impact of Cd(II) on the stability of human uracil DNA glycosylase enzyme; an implication of molecular dynamics trajectories on stability analysis

Abstract

Uracil DNA glycosylase is a key enzyme that identifies and removes damaged bases from DNA in the base excision repair pathway. Experimentalists have identified the possibility of Cd(II) reducing the activity of human uracil DNA glycosylase (hUNG) by binding with the enzyme replacing the catalytic water molecule. The present study focus on the stability variation of the enzyme in the presence and absence of Cd(II) and confirms the reported results with the stability analysis done using molecular dynamic (MD) simulation trajectories. The CavityPlus web server identified seven cavities for the free enzyme as possible binding sites and a cavity containing the active site of the enzyme as the best binding cavity for a ligand. Based on the CavityPlus results and the previously reported work, a free hUNG system and two systems of the enzyme with Cd(II); one with Cd(II) replacing the catalytic water molecule in the active site of the enzyme and the other replacing a non-catalytic water molecule in the active site were generated for the simulation. The simulation trajectories were used for the structural stability analysis of the enzyme in all three systems. The binding free energy of the Cd(II) with the enzyme was calculated using molecular mechanics Poisson Boltzmann surface area method. The results showed that the enzyme achieves comparatively high stability with the removal of catalytic water of the enzyme by Cd(II). Therefore, this supports the previously reported idea that Cd(II) replaces catalytic water molecules and affects enzyme activity.

Graphical Abstract

HIGHLIGHTS

• Cd(II) can replace the catalytic water molecule found in the active site of hUNG.

• The binding of Cd(II) makes the hUNG-Cd(II) system stable.

• The compactness of hUNG with Cd(II) increases with the decrease of Rg; hence, stability increases compared to free hUNG.

• The dynamical behavior of residues of free hUNG gets reduced in the presence of the Cd(II) ion.

• The activity of hUNG gets affected with the replacement of catalytic water by Cd(II).

Communicated by Ramaswamy H. Sarma

Keywords:

• Human uracil DNA glycosylase
• molecular dynamic simulation
• CavityPlus web server
• structural stability
• MMPBSA

Acknowledgements

This research work is dedicated to the remembrance of the late Prof. S. Maheswaran, an eminent scientist, chemist, academic, and science administrator in Sri Lanka, on the occasion of his twenty-fourth death anniversary.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Accelerating Higher Education Expansion and Development (AHEAD) Operation, Sri Lanka. Development Orientated Research Grant No 28. The Open University of Sri Lanka.