Ligand migration and protein dynamics in the globin family

D.A. ESTRIN

Buzios

Conferencia; II Latin American Federation of Biophysical Societies; 2012

Brazilian Biophysical Society

LIGAND MIGRATION AND PROTEIN DYNAMICS IN THEGLOBIN FAMILYDarío A. EstrinDepartamento de Química Inorgánica, Analítica y Química Física, and INQUIMAE-CONICET,Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, ArgentinaGlobins are globular proteins typically comprising eight α-helical segments (named A-H) that display a3-over-3 α-helical sandwich structure. The globin protein superfamily also includes truncated versions(trHbs) whose fold consists of only four α-helices. Globins contain a heme prosthetic group, by whichthey can reversibly bind ligands like O2, CO, NO, and H2S. Ligand entry to the active site is typicallythe key process to understand globin reactivity and has been the subject of numerous experimental andtheoretical studies. In this work we will present results for ligand migration and globin dynamics in twoparadigmatic cases by using molecular dynamics simulations and advanced sampling tools.(i) Histidine gate in myoglobin (Mb). Since the discovery of Mb structure, a histidine residue on the Ehelix in position 7 (HisE7) has been proposed to act as a gate for ligand entry and escape. Thishypothesis assumes the existence of a closed and an open conformation for the histidine side chain. Weinvestigated the influence of the protonation and conformational states of HisE7 on oxygen migrationthrough this pathway. By calculating free energy profiles we found that the so-called HisE7 gate is notable to create a considerable barrier to block ligand migration. Instead, we highlight the importance of ahydrophobic site close to the iron center that stabilizes oxygen and drives oxygen migration through theE7 pathway.(ii) Ligand migration in trHbN of M. Tuberculosis. M. tuberculosis has evolved a defense againstnitrosative stress that relies on the NO-dioxygenase activity of trHbN. X-ray structures have shownthat trHbN hosts a two-branched tunnel system, proposed to control ligand migration to the heme. Oursimulations suggest that O2 migration in deoxy-trHbN is restricted to the short branch of the tunnel,and that O2 binding to the heme drives conformational fluctuations promoting NO migration throughthe long tunnel branch. The simulation results suggest that trHbN has evolved a dual-path mechanismfor ligand migration to the heme, to achieve efficient NO detoxification.