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

Abstract

Molecular dynamics simulations were applied to human 5-LOX to obtain detailed information on its structure and dynamics with and without ligands. The dynamical properties evaluated based on root mean square deviations, root mean square fluctuations and secondary structure prediction helped decipher the contrast dynamic behavior of the systems pointing toward the ligand binding effect. The ligand binding to the protein also perturbed other properties of the protein such as the central bending of the protein and water coordination to the metal ion. The central bending in the protein was reported to be very significant that was associated with the allosteric modulation in the lipoxygenases; therefore, on a similar line, the central bending was evaluated in terms of hinge angle analysis which showed substantial bending between the C-terminal and the N-terminal domain via the linker residues which connects the two domains. On the other hand, the suspected water coordination to the metal ion in the protein was ruled out by computing the iron-water radial distribution function which showed that the water molecule was not found to be in the vicinity of the metal ion. Finally, the binding free energy was estimated for Zileuton and CAPE1 inhibitors bound to 5-LOX via the thermodynamic integration approach which showed that CAPE1 had a strong binding potential for the active site of the protein compared to Zileuton, and the free energy data correlated well with their IC50 values corresponding to the high inhibition potential of CAPE1 compared to Zileuton.