Anthrax Lethal Factor Investigated by Molecular Simulations.

The anthrax disease is caused by the lethal toxin secreted by the bacterium Bacillus anthracis. The toxin is a protein aggregate which contains a Zn-based hydrolase called anthrax Lethal Factor (LF). In this work, we investigate the structure of its Michaelis complex with an optimized MAPKK-like substrate using several computational methods including density functional theory, molecular dynamics, and coarse grained techniques. Our calculations suggest that (i) the presence of second-shell ligands is crucial for tuning the structure, energetics, and protonation state of the metal binding site, as found in other Zn-based enzymes; (ii) the nucleophilic agent is a Zn-bound water molecule; (iii) substrate binding to the active site groove is mainly stabilized by van der Waals interactions; (iv) the bonds most likely involved in the substrate hydrolysis are only mildly polarized by the protein scaffold; and (v) part of helix α19, which is present in one solid state structure of LF (PDB: 1JKY ), assumes a coiled conformation.