Mechanism of inhibition of polymerization by HbF. (A) Dissociation of tetramers into dimers and reassociation in mixtures of HbS and HbF result in 3 tetramers in a binomial distribution, thereby further lowering the fraction of the HbS homotetramer (α₂β^S₂).⁵⁷  (B) Cartoon of polymerization equilibrium in HbS-HbF mixture. As in a crystallization reaction, Hb tetramers are present in 2 phases: the solution phase (left) or the fiber phase (right). The fibers that form in these mixtures are primarily composed of the HbS homotetramers, but there is also some copolymerization of hybrid tetramers (α₂β^Sγ) (half-green, half-empty circles).^35,58  (C) Cartoon of F cell with 30% HbF and 70% HbS. The excluded volume effect of the non-copolymerizing α₂γ₂ tetramer (green-filled circles) and partially copolymerizing tetramer α₂β^Sγ (half-green, half-empty circles) increases the activity of the polymerizing α₂β^S₂ homotetramer (empty circles). (D) Activity coefficient (γ) as a function of total Hb concentration. The dimensionless activity coefficient is the factor that multiplies the measured concentration (ie, moles per liter or grams per deciliter) to obtain the activity, which is the thermodynamically effective concentration.⁵⁹