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A Precision Medicine Tool for Measurement and Monitoring of Hemoglobin S in Sickle Cell Disease Patients Receiving Transfusion Therapy
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Dissecting the energies that stabilize sickle hemoglobin polymers
1Department of Physics, Drexel University, Philadelphia, Pennsylvania.
Biophysical Journal
|November 12, 2013
Summary
Sickle hemoglobin (HbS) polymer formation is driven by lateral contacts involving the mutation site, which are stronger than axial contacts. This explains HbS pathophysiology and suggests significant dimer association at physiological conditions.
Area of Science:
- Biophysics
- Molecular Biology
- Hematology
Background:
- Sickle hemoglobin (HbS) polymerizes, causing sickle cell disease pathophysiology.
- Polymerization involves axial and lateral molecular contacts.
- Lateral contacts engage the HbS mutation site, unlike axial contacts.
Purpose of the Study:
- To investigate the association process of sickle hemoglobin.
- To compare the thermodynamics of HbS polymerization with nonpolymerizable hemoglobins.
- To elucidate the role of different contact types in HbS polymer formation.
Main Methods:
- Elastic light scattering measurements.
- Variable temperature and concentration studies.
- Analysis of primary and quaternary protein structure.
Main Results:
- Deoxy HbS shows significantly greater association than COHbS, COHbA, and deoxygenated HbA.
- Axial contacts are weaker than lateral contacts, which involve the mutation site.
- All associations are entropically favored and enthalpically disfavored, indicative of hydrophobic interactions.
Conclusions:
- Lateral contacts are crucial for HbS polymerization.
- Thermodynamic data align with polymer assembly models, indicating similar dimer and polymer contacts.
- A significant portion of hemoglobin likely exists as dimers under physiological conditions.
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