Catalytic mechanism of C-F bond cleavage: insights from QM/MM analysis of fluoroacetate dehalogenase

The catalytic mechanisms of fluoroacetate dehalogenase (FAcD) toward substrates fluoroacetate and chloroacetate were studied by a combined quantum mechanics/molecular mechanics (QM/MM) method. There are twenty snapshots considered for each of the three individual systems. By analyzing multiple independent snapshots, positive or negative relationships between energy barriers and structural parameters in defluorination and dechlorination processes were established. We have also shown that conformational variations may cause enzymatic preference differences toward competitive pathways. Besides residues Arg111, Arg114, His155, Trp156, and Tyr219, the importance of residues His109, Asp134, Lys181, and His280 during the defluorination process were also highlighted through electrostatic analysis. These results may provide clues for designing new biomimetic catalysts toward degradation of fluorinated compounds.