Double strand packing in hemoglobin S fibers

Area of Science:

• Biochemistry
• Structural Biology
• Hematology

Background:

• Sickle cell disease is caused by a variant of human hemoglobin, Hb S (beta 6 Glu-->Val).
• Hb S molecules polymerize into 14-strand helical fibers, crucial for disease pathology.
• Understanding the precise molecular arrangement within these fibers is key to therapeutic strategies.

Purpose of the Study:

• To compare different structural models of Hb S fibers based on recent crystallographic and fiber diffraction data.
• To determine which structural model best explains the intermolecular contacts and overall packing within Hb S fibers.
• To correlate structural findings with experimental observations on Hb S stability and polymerization.

Main Methods:

• Analysis of intermolecular contacts in Hb S fibers using published data from Carragher et al. and Dykes et al./Rodgers et al.
• Comparison of two distinct structural models: one suggesting loose packing and another suggesting closer packing of double strands.
• Evaluation of the number and significance of potential contacts between double strands within the helical fiber structure.

Main Results:

• Significant discrepancies were found between the structural models derived from Carragher et al. data (loose packing) and Dykes-Rodgers et al. data (closer packing).
• The loose packing model identified only four significant contacts out of 11 potential classes between double strands.
• The closer packing model, based on Dykes-Rodgers data, revealed nine significant contacts within 5 Å, indicating a more compact structure.

Conclusions:

• The structural model proposing closer packing of double strands in Hb S fibers shows better agreement with other experimental results.
• This finding has implications for understanding the mechanism of Hb S polymerization and the stability of sickle cell fibers.
• Further refinement of the Hb S fiber structure is needed to fully elucidate its assembly and pathological role.