Mechanism of proteolysis of anthrax lethal factor. An ab initio and hybrid QM/MM molecular dynamics study

The disease anthrax is caused by lethal factor (LF), an enzyme component of the toxin produced by the bacterium Bacillus Anthracis. Our studies are devoted to shed light on the binding and proteolytic mechanism of MAPKK kinase family promoted by anthrax lethal factor. At first, based on the X-ray structure of LF we have provided an understanding of the structural determinants and the hydrogen bond network that surrounds the LF active site, using static and dynamic density functional (DFT) calculations. Subsequently, classical molecular dynamics simulations have been performed on the entire protein structure and the solvent waters in order to clarify the binding and the specific substrate-protein interactions of MAPKK to the active site of LF. Finally, hybrid quantum/classical (QM/MM) molecular dynamics simulations have been performed on the entire protein structure and the solvent in order to understand the exact mechanism by which LF cleaves the NH2-termini of the MAPK-kinase family.