| Abstract
| - Macrophage migration inhibitory factor (MIF) exhibits tautomerase activity on phenylpyruvateand has E-stereochemistry preference. To investigate the binding modes of its competitiveinhibitors and evaluate their binding affinities, molecular dynamics simulations together withMM-PBSA (molecular mechanics Poisson−Boltzmann surface area) analysis were performedon MIF complexed with (E)-2-fluoro-p-hydroxycinnamate and five analogues. Pro-1 wasdiscovered to form a bifurcated hydrogen bond between its protonated nitrogen and carboxylateoxygens of E-ligands and Tyr-36. No hydrogen bonds were found between Pro-1 and Z-ligands.This distinct binding characteristic of E- and Z-ligands with Pro-1 may be the main factor forthe large difference in their binding affinities, which is consistent with the previous reportthat Pro-1 is essential for the catalytic activity of MIF. MM-PBSA analysis revealed that energycomponents including van der Waals, electrostatic, and hydrophobic interactions are in favorof binding, among which electrostatic interactions are predominant to the binding affinitydifference.
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