Inhibitor binding by metallo-beta-lactamase IMP-1 from Pseudomonas aeruginosa: quantum mechanical/molecular mechanical simulations.

The dynamics of the IMP-1 enzyme complexed with three prototypical inhibitors are investigated using a quantum mechanical/molecular mechanical (QM/MM) method based on the self-consistent-charge density-functional tight-binding model. The binding patterns of the inhibitors observed in X-ray diffraction experiments are well reproduced in 600 ps molecular dynamics simulations at room temperature. These inhibitors anchor themselves in the enzyme active site by direct coordination with the two zinc ions, displacing the hydroxide nucleophile that bridges the two zinc ions. In addition, they also interact with several active-site residues and those in two mobile loops. The excellent agreement with experimental structural data validates the QM/MM treatment used in our simulations.