Simulated Mechanism of Triclosan in Modulating the Active Site and Loop of FabI by Computer

The impact of conformation of the active site loop, secondary structure, active site volume, and substrate (unsaturated acyl chain) channel as a function of simulation time caused by the FabI (enoyl-ACP reductase) inhibitor of triclosan were studied by molecular dynamics simulations, define secondary structure of proteins (DSSP), and pocket volume measurer (POVME). Triclosan restricted the changes of the active site and substrate channel of the FabI-NAD(+)-TCL (NAD(+) : nicotinamide adenine dinucleotide, TCL: triclosan) ternary complex. The active site loop formed an ordered, closed, and stable conformation, and was commonly associated with a helical structure in front of the active site. This made the active site volume change little, the volume distribution concentrated and the substrate channel size narrowed and almost closed. However, the active site loop was disordered, open, and flexible in the FabI-NAD(+) binary complex. The changes of active site volume and distribution in the binary system were larger and more disperse than those in the ternary system. The substrate channel size in the binary system widened and became unstable. Triclosan induced residues of the active site and active site loop of FabI and made the ternary system more closed, which blocked the unsaturated acyl chains from getting into the catalytic center of FabI through the substrate channel, interrupted the reduction reaction and the elongation cycle of fatty acid synthesis. These results aid our understanding of potent inhibitory activity of triclosan and related compounds.