INQUIMAE   12526
INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
artículos
Título:
Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7
Autor/es:
L. BOECHI; M. ARRAR; M.A. MARTI; J.S. OLSON; A.E. ROITBERG; D.A. ESTRIN
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Editorial:
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Referencias:
Lugar: Bethesda, Maryland; Año: 2013 vol. 288 p. 6754 - 6762
ISSN:
0021-9258
Resumen:
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.