Structural and dynamical correlations in PfHGXPRT oligomers: A molecular dynamics simulation study.

Area of Science:

• Biochemistry and Molecular Biology
• Parasitology
• Structural Biology

Background:

• Plasmodium falciparum hypoxanthine-guanine phosphoribosyltransferase (PfHGXPRT) is vital for purine metabolism in the malaria parasite.
• Understanding PfHGXPRT enzyme dynamics is key to developing new antimalarial drugs.

Purpose of the Study:

• To investigate the dynamic behavior of PfHGXPRT dimers (D1, D3) and tetramers using atomistic molecular dynamics simulations.
• To elucidate the role of enzyme conformational changes, particularly loop dynamics, in ligand binding and catalytic activity.

Main Methods:

• Atomistic molecular dynamics simulations were performed on apo and ligand-bound states of PfHGXPRT dimers (D1, D3) and tetramers.
• Analysis focused on the conformational changes of active site loops (II and IV) and remote loop X.

Main Results:

• Active site loop II dynamics are significant and stabilize upon ligand binding through specific residue-ligand interactions.
• Remote loop X exhibits reduced flexibility in the D3 dimer compared to D1 due to increased inter-subunit contacts.
• Ligand binding in the tetramer reduces loop X flexibility, indicating communication between remote regions and active sites.

Conclusions:

• PfHGXPRT enzyme dynamics, particularly loop movements, are intrinsically linked to its catalytic cycle and ligand interactions.
• The D1 dimer readily tetramerizes, suggesting its prevalence as a tetramer in solution, while D3 exists in equilibrium with the tetramer.
• Ligand binding influences PfHGXPRT oligomerization state, potentially shifting the equilibrium towards the tetrameric form.