Shadrina, Maria S.; Peslherbe, Gilles H.; English, Ann M.
Quaternary-Linked Changes in Structure and Dynamics That Modulate O-2 Migration within Hemoglobin's Gas Diffusion Tunnels
BIOCHEMISTRY, 54:5268-5278, SEP 1 2015

Atomistic molecular dynamics simulations of diffusion of O-2 from the hemes to the external solvent in the alpha- and beta-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 O-2 population in the cavities and the preferred O-2 escape portals Vary significantly with quaternary structure. For example, most O-2 molecules escape from the T beta-subunit via the cavity at the center of the tetramer, but direct exit from the distal heme pocket dominates in the R2 beta-subunit. To understand what triggers the quaternary-linked redistribution of O-2 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 a-chain dynamics and beta-heme position. modulate O-2 distribution and escape in FibA. Coupled to the beta-heme,position, residue beta 71 undergoes quaternary-linked conformations that strongly regulate O-2 migration between the beta-subunit and HbA's central cavity. Remarkably, the distal histidine (HisE7) remains in a closed conformation near the alpha- and beta-hemes in all states, but this does not prevent an average of 23, 31, and 46% of O-2 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 O-2 to selected-cavities by mutating HisE7 and other heme pocket residues to tryptophan reveals how O-2 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, and R2 quaternary States and provide new mechanistic insights into why undergoing transitions among these states likely ensures effective O-2 delivery by this tetrameric protein.

DOI:10.1021/acs.biochem.5b00368

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