Computational Studies of the Catalytic Mechanism of the Staphylococcus Aureus Sortase a Enzyme

Abstract

When surface proteins are attached to the cell wall of Gram-positive bacteria, they play important roles in multiple pathogens such as pneumonia, meningitis, osteomyelitis, and so on. Class A sortase (SrtA) enzymes play a key role in the insertion of surface proteins into the cell wall. StrA recognizes an LPXTG sorting signal motif in a target protein and catalyzes a transpeptidation reaction that joins it to a Lipid II molecules that will be embedded into the cell wall. Bacteria strains that lack SrtA are incapable of placing surface proteins, suggesting that SrtA may be a novel drug target for therapeutics against Gram-positive bacteria. However, the precise mechanism of transpeptidation is not well understood because of the unstable catalytic intermediates. Here we report on a series of molecular dynamics simulations using a hybrid quantum mechanical/molecular mechanics (QM/MM) approach to investigate the catalytic mechanism of SrtA.