Mechanism of polymerization inhibition by increasing oxygen affinity. (A) Hemoglobin exists in a rapidly reversible equilibrium between low- and high-affinity quaternary conformations, called T and R, respectively.^65,66  They differ primarily by an ∼15° relative rotation of αβ dimers. Location of β6 valine is shown as a yellow dot on the surface of the molecule. Preferential binding of a small molecule such as a drug (red circle) to R shifts the quaternary equilibrium toward R. (B) Cartoon of polymerization equilibrium. Only the T quaternary structure (empty circles) enters the fiber. R quaternary conformations (filled circles) are completely excluded.⁶⁹  (C) Oxygen binding curves. Preferential binding of a drug to the R quaternary structure causes a left shift (increased oxygen affinity).