Structure and dynamics of 5-lipoxygenase and its complexes - a molecular dynamics simulation study

Area of Science:

• Biochemistry
• Structural Biology
• Computational Chemistry

Background:

• Human 5-lipoxygenase (5-LOX) is a key enzyme in leukotriene biosynthesis.
• Understanding 5-LOX structure and dynamics is crucial for developing inhibitors.

Purpose of the Study:

• To investigate the structural and dynamic effects of ligand binding on human 5-LOX.
• To compare the binding affinities of Zileuton and CAPE1 inhibitors to 5-LOX.

Main Methods:

• Molecular dynamics (MD) simulations were performed on human 5-LOX.
• Analysis included root mean square deviation (RMSD), root mean square fluctuation (RMSF), and secondary structure prediction.
• Hinge angle analysis and radial distribution functions were used to assess protein dynamics and metal ion coordination.
• Binding free energies were calculated using thermodynamic integration.

Main Results:

• Ligand binding significantly altered the dynamic behavior and central bending of 5-LOX.
• Hinge angle analysis revealed substantial bending between the N-terminal and C-terminal domains.
• Water coordination to the iron metal ion was ruled out.
• CAPE1 exhibited stronger binding potential to 5-LOX than Zileuton, consistent with their IC50 values.

Conclusions:

• Ligand binding induces significant conformational changes in human 5-LOX.
• CAPE1 is a more potent inhibitor of 5-LOX compared to Zileuton.
• MD simulations provide valuable insights into 5-LOX inhibition mechanisms.