Quaternary-Linked Changes in Structure and Dynamics That Modulate O2 Migration within Hemoglobin's Gas Diffusion Tunnels.
Biochemistry
; 54(34): 5268-78, 2015 Sep 01.
Article
en En
| MEDLINE
| ID: mdl-26226318
ABSTRACT
Atomistic molecular dynamics simulations of diffusion of O2 from the hemes to the external solvent in the α- and ß-subunits of the human hemoglobin (HbA) tetramer reveal transient gas tunnels that are not seen in crystal structures. We find here that the tunnel topology, which encompasses the reported experimental Xe binding cavities, is identical in HbA's T, R, and R2 quaternary states. However, the O2 population in the cavities and the preferred O2 escape portals vary significantly with quaternary structure. For example, most O2 molecules escape from the T ß-subunit via the cavity at the center of the tetramer, but direct exit from the distal heme pocket dominates in the R2 ß-subunit. To understand what triggers the quaternary-linked redistribution of O2 within its tunnels, we examined how the simulated tertiary structure and dynamics of each subunit differs among T, R, and R2 and report that minor adjustments in α-chain dynamics and ß-heme position modulate O2 distribution and escape in HbA. Coupled to the ß-heme position, residue ßF71 undergoes quaternary-linked conformations that strongly regulate O2 migration between the ß-subunit and HbA's central cavity. Remarkably, the distal histidine (HisE7) remains in a closed conformation near the α- and ß-hemes in all states, but this does not prevent an average of 23, 31, and 46% of O2 escapes from the distal heme pockets of T, R, and R2, respectively, via several distal portals, with the balance of escapes occurring via the interior tunnels. Furthermore, preventing or restricting the access of O2 to selected cavities by mutating HisE7 and other heme pocket residues to tryptophan reveals how O2 migration adjusts to the bulky indole ring and sheds light on the experimental ligand binding kinetics of these variants. Overall, our simulations underscore the high gas porosity of HbA in its T, R, and R2 quaternary states and provide new mechanistic insights into why undergoing transitions among these states likely ensures effective O2 delivery by this tetrameric protein.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oxígeno
/
Hemoglobina A
Límite:
Humans
Idioma:
En
Revista:
Biochemistry
Año:
2015
Tipo del documento:
Article
País de afiliación:
Canadá