Biophysical Basis of Hb-S Polymerization in Red Blood Cell Sickling

Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by the Glu6Val mutation in the {beta} chain (Hb) of the oxygen-carrying hemoglobin protein in sicklemia patients. In the molecular pathogenesis of SCD, the sickle hemoglobin (Hb-S) polymerization is a major driver for structural deformation of red blood cells, i.e. red blood cell (RBC) sickling. Biophysically, it still remains elusive how this SCD-linked E6V mutation leads to Hb-S polymerization in RBC sickling. Therefore, with a comprehensive set of analysis of experimental Hb structures, this letter highlights electrostatic repulsion as a key biophysical mechanism of Hb-S polymerization in RBC sickling, which provides atomic-level insights into the functional impact of the SCD-linked E6V substitution from a biophysical point of view.\n\nSIGNIFICANCEDuring the past 25 years, a total of 104 Hb-related structures have been deposited in PDB. For the first time, this article presents a comprehensive set of electrostatic analysis of the 104 experimental structures, highlighting electrostatic repulsion as a fundamental biophysical mechanism for Hb-S polymerization in RBC sickling. The structural and electrostatic analysis here also provides biophysical insights into the functional impact of the SCD-linked E6V substitution.