MD Simulation of Ligand Migration and Substrate Binding in Lipoxygenases*

Lipoxygenases are an important class of enzymes with non-haem, non-sulphur iron-containing protein, whose catalytic
action has severe consequences in a range of inflammatory diseases and its associated disease. The lipoxygenases are responsible for catalyzing the activation of poly-unsaturated fatty acids by inserting molecular oxygen at a specific position of the substrate, in a highly stereo-specific and regio-specific manner to yield hydro-peroxide [1]. We are currently investigating the pathways of migration of oxygen molecule into the active site of the enzyme and trying to determine the binding modes of the substrate. We have identified the side chains, such as, Arg185, Tyr181, Phe178, Ala592, Ala623, and Leu434 to play an important role in substrate binding. We are investigating the substrate binding propensity for different mutant systems and their roles towards hydroperoxidation. Further, we are investigating the global dynamic of the protein at atomic level. We are interested in providing a detailed description of the reaction pathway with structural and energetic details of the reactants, products, and intermediates along with the transition states separating them.

[1] M. Kobe, D. Neau, C. Mitchell, and M. Newcomer, J. Biol. Chem. 289, 31905 (2014).