title: Hydrophobic effect drives oxygen uptake in myoglobin via histidine E7.
abstract: Since the elucidation of the myoglobin (Mb) structure, a histidine residue on the E helix (His-E7) has been proposed to act as a gate with an open or closed conformation controlling access to the active site. Although it is believed that at low pH, the His-E7 gate is in its open conformation, the full relationship between the His-E7 protonation state, its conformation, and ligand migration in Mb is hotly debated. We used molecular dynamics simulations to first address the effect of His-E7 protonation on its conformation. We observed the expected shift from the closed to the open conformation upon protonation, but more importantly, noted a significant difference between the conformations of the two neutral histidine tautomers. We further computed free energy profiles for oxygen migration in each of the possible His-E7 states as well as in two instructive Mb mutants: Ala-E7 and Trp-E7. Our results show that even in the closed conformation, the His-E7 gate does not create a large barrier to oxygen migration and permits oxygen entry with only a small rotation of the imidazole side chain and movement of the E helix. We identify, instead, a hydrophobic site in the E7 channel that can accommodate an apolar diatomic ligand and enhances ligand uptake particularly in the open His-E7 conformation. This rate enhancement is diminished in the closed conformation. Taken together, our results provide a new conceptual framework for the histidine gate hypothesis.
authors.affiliation: Departamento de Química Inorgánica, Analítica, y Química Física/Inquimae-Conicet, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. Ciudad Universitaria, Pabellon 2, C1428EHA Buenos Aires, Argentina.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Boechi
authors.forename: Mehrnoosh
authors.initials: M
authors.lastname: Arrar
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Martí
authors.forename: John S
authors.initials: JS
authors.lastname: Olson
authors.forename: Adrián E
authors.initials: AE
authors.lastname: Roitberg
authors.forename: Darío A
authors.initials: DA
authors.lastname: Estrin
mesh_terms: D000818:Animals; D006639:Histidine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D009211:Myoglobin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary
chemical_list: D009211:Myoglobin; D006639:Histidine; D010100:Oxygen