Mycobacterium tuberculosis, the causative agent of human
tuberculosis, is forced into latency by
nitric oxide produced by macrophages during
infection. In response to nitrosative stress M.
tuberculosis has evolved a defense mechanism that relies on the oxygenated form of "
truncated hemoglobin" N (trHbN), formally acting as
NO-dioxygenase, yielding the harmless
nitrate ion. X-ray crystal structures have shown that trHbN hosts a two-branched
protein matrix tunnel system, proposed to control diatomic
ligand migration to the
heme, as the rate-limiting step in NO conversion to
nitrate. Extended molecular dynamics simulations (0.1 micros), employed here to characterize the factors controlling diatomic
ligand diffusion through the apolar tunnel system, suggest that O2 migration in deoxy-trHbN is restricted to a short branch of the tunnel, and that O2 binding to the
heme drives conformational and dynamical fluctuations promoting NO migration through the long tunnel branch. The simulation results suggest that trHbN has evolved a dual-path mechanism for migration of O2 and NO to the
heme, to achieve the most efficient NO detoxification.