Abstract:
:Sickle hemoglobin forms long, multistranded polymers that account for the pathophysiology of the disease. The molecules in these polymers make significant contacts along the polymer axis (i.e., axial contacts) as well as making diagonally directed contacts (i.e., lateral contacts). The axial contacts do not engage the mutant β6 Val and its nonmutant receptor region on an adjacent molecule, in contrast to the lateral contacts which do involve the mutation site. We have studied the association process by elastic light scattering measurements as a function of temperature, concentration, and primary and quaternary structure, employing an instrument of our own construction. Even well below the solubility for polymer formation, we find a difference between the association behavior of deoxy sickle hemoglobin molecules (HbS), which can polymerize at higher concentration, in comparison to COHbS, COHbA, or deoxygenated Hemoglobin A (HbA), none of which have the capacity to form polymers. The nonpolymerizable species are all quite similar to one another, and show much less association than deoxy HbS. We conclude that axial contacts are significantly weaker than the lateral ones. All the associations are entropically favored, and enthalpically disfavored, typical of hydrophobic interactions. For nonpolymerizable Hemoglobin, ΔH(o) was 35 ± 4 kcal/mol, and ΔS was 102.7 ± 0.5 cal/(mol-K). For deoxyHbS, ΔH(o) was 19 ± 2 kcal/mol, and ΔS was 56.9 ± 0.5 cal/(mol-K). The results are quantitatively consistent with the thermodynamics of polymer assembly, suggesting that the dimer contacts and polymer contacts are very similar, and they explain a previously documented significant anisotropy between bending and torsional moduli. Unexpectedly, the results also imply that a substantial fraction of the hemoglobin has associated into dimeric species at physiological conditions.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Wang Y,Ferrone FAdoi
10.1016/j.bpj.2013.09.032subject
Has Abstractpub_date
2013-11-05 00:00:00pages
2149-56issue
9eissn
0006-3495issn
1542-0086pii
S0006-3495(13)01080-1journal_volume
105pub_type
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