An α-chain modification rivals the effect of fetal hemoglobin in retarding the rate of sickle cell fiber formation.

Adults with sickle cell disease bear a mutation in the ß-globin gene, leading to the expression of sickle hemoglobin (HbS; α2ßS2). Adults also possess the gene for γ-globin, which is a component of fetal hemoglobin (HbF, α2γ2); however, γ-chain expression normally ceases after birth. As HbF does not form the fibers that cause the disease, pharmacological and gene-modifying interventions have attempted to either reactivate expression of the γ chain or introduce a gene encoding a modified ß chain having γ-like character. Here, we show that a single-site modification on the α chain, αPro114Arg, retards fiber formation as effectively as HbF. Because this addition to the repertoire of anti-sickling approaches acts independently of other modifications, it could be coupled with other therapies to significantly enhance their effectiveness.

Entropy of Charge Inversion in DNA including One-Loop Fluctuations.

The entropy and charge distributions have been calculated for a simple model of polyelectrolytes attached to the surface of DNA using a field-theoretic method that includes fluctuations to the lowest one-loop order beyond mean-field theory. Experiments have revealed correlation-driven behavior of DNA in charged solutions, including charge inversion and condensation. In our model, the condensed polyelectrolytes are taken to be doubly charged dimers of length comparable to the distance between sites along the phosphate chains. Within this lattice gas model, each adsorption site is assumed to have either a vacancy or a positively charged dimer attached with the dimer oriented either parallel or perpendicular to the double-helix DNA chain. We find that the inclusion of the fluctuation terms decreases the entropy by ∼50% in the weak-binding regime. There, the bound dimer concentration is low because the dimers are repelled from the DNA molecule, which competes with the chemical potential driving them from the solution to the DNA surface. Surprisingly, this decrease in entropy due to correlations is so significant that it overcompensates for the entropy increase at the mean-field level, so that the total entropy is even lower than in the absence of interactions between lattice sites. As a bonus, we present a transparent exposition of the methods used that could be useful to students and others wishing to use this formulation to extend this calculation to more realistic models.

The Sickle-Cell Fiber Revisited.

Sickle cell disease is the consequence of a single point mutation on the surface of the ß chains of the hemoglobin molecule leading to the formation of rigid polymers that disrupt circulation. It has long been established that the polymers are comprised of seven pairs of double strands that are twisted replicas of the double strands found in crystals. Here, we review several newer developments that elaborate on that simple model and provide deeper insights into the process.

Lattice-gas model of DNA charge inversion by a positively charged polyelectrolyte.

The model of DNA charge inversion by Nguyen and Shklovskii [T. T. Nguyen and B. I. Shklovskii, Phys. Rev. Lett. 89, 018101 (2002)] is extended. A single double-helix strand of DNA is represented by a lattice of negative charges at the positions of the protruding oxygens of the phosphates along the DNA backbone, and the adsorbed polyelectrolyte molecules are represented by charged dimers. A lattice-gas model is used in which dimers adsorbing either parallel or perpendicular to the lattice are treated as separate species, and the model allows for vacancies between adsorbed species. The mean field theory used is formulated as a saddle-point approximation of the exact functional integral representation of the grand canonical partition function, opening the way for the inclusion of the effects of charge fluctuation corrections.