title: Exploring the molecular basis of heme coordination in human neuroglobin.
abstract: Neuroglobin (Ngb), a recently discovered ancient heme protein, presents the typical globin fold and is around 20% identical to myoglobin (Mb). In contrast with Mb, however, its heme is hexacoordinated (6c). It is expressed in the nervous system and has been the subject of numerous investigations in the last years, but its function is still unclear. The proposed roles include oxygen transport, reactive oxygen species (ROS) detoxification, hypoxia protection, and redox state sensing. All proposed functions require distal histidine dissociation from the heme to yield a reactive iron. With the aim of understanding the 6c to 5c transition, we have performed molecular dynamics simulations for ferrous Ngb in the 6c, 5c, and oxy states. We also computed free energy profiles associated with the transition employing an advanced sampling technique. Finally, we studied the effect of the redox state of CysCD7 and CysD5, which are known to form a disulfide bridge. Our results show that protein oxidation promotes a stabilization of the pentacoordinated species, thus favoring the protein to adopt the more reactive state and supporting the existence of a molecular mechanism whereby O2 would be released under hypoxic conditions, thereby suggesting an O(2) storage function for Ngb. Taken together, our results provide structural information not available experimentally which may shed light on the protein proposed functions, particularly as a redox sensor.
authors.affiliation: Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, Buenos Aires (C1428EHA), Argentina.
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Nadra
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Martí
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pesce
authors.forename: Martino
authors.initials: M
authors.lastname: Bolognesi
authors.forename: Darío A
authors.initials: DA
authors.lastname: Estrin
mesh_terms: D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005914:Globins / Q000737:chemistry*; D006418:Heme / Q000737:chemistry*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D000078787:Neuroglobin; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D008024:Ligands; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D006418:Heme; D006639:Histidine; D005914:Globins