Free heme in micromolar amounts enhances the attraction between sickle cell hemoglobin molecules

We probe the role of free heme in the interactions between sickle cell hemoglobin (HbS) molecules in simulated physiological solutions: polymerization of deoxy-HbS is the primary pathogenic event of sickle cell anemia, and HbS releases heme after autoxidation more readily than normal adult hemoglobin. We characterize these interactions in terms of osmotic virial coefficients, which we determine by static light scattering. We analyze the results in the heme-hemoglobin system using the Kirkwood-Goldberg model. We show that in the absence of heme, the HbS molecules weakly attract and the attraction is not due to the lowered-as a result of the sickle cell mutation-molecular charge. We show that the part of the interface between the two alphabeta dimers, exposed in the deoxy-state, plays a crucial role in this attraction. We show that heme at micromolar concentrations induces strong attraction between the hemoglobin molecules. We show that the high efficacy of the heme results from the statistics of electrostatic and hydrophobic interactions between the heme and hemoglobin molecules.