Simulated formation of polymer domains in sickle hemoglobin

Abstract

Using experimentally observed processes of linear growth, heterogeneous nucleation, and polymer bending, with no additional assumptions, we have been able to model the two-dimensional formation of polymer domains by sickle hemoglobin. The domains begin with twofold symmetry and proceed toward closure into spherulites at a constant rate. Relationships derived from the simulations presented and the requirements of scaling result in simple expressions for the sensitivity of the closure times to the model input parameters and allow the results to be extended to regions not actually simulated. For concentrations above approximately 25 g/dl, closure times are longer than the time required for the conclusion of the polymerization reaction, and thus incomplete spherulites will be the dominant geometry at high concentrations. Moreover, spherulites are not predicted to form in times less than a few seconds, implying that spherulites will not form during the transit of erythrocytes through the capillaries. Polymer-polymer exclusion, surface nucleation, and monomer exhaustion were also explored and found to have only weak effects on the results.

Predicting the morphology of sickle red blood cells using coarse-grained models of intracellular aligned hemoglobin polymers

“…On the contrary, the angular widening of the polymer domain, originated from the fiber branching, is largely suppressed for smaller heterogeneous nucleation rate as observed in both experiments 14 and numerical simulations. 15 Remarkably, this tendency is also consistent with the inverse relationship between the amount of intracellular aligned hemoglobin polymer and the mean corpuscular hemoglobin concentration values for each class of cells (categorized by the total number of polymer domains) reported in ref. 9.…”

“…This configuration prevails with the physiological conditions of low mean corpuscular hemoglobin concentration value and slow deoxygenation rate, where the sickle hemoglobin heterogeneous nucleation is largely suppressed, as observed in experiments 9 and predicted by simulations. 15 Accordingly, we choose the mean corpuscular hemoglobin concentration value as 32 g dL −1 , where the bulk growth rate is 1.2 × 10 4 molecules s −1 . Moreover, we note that the aligned hemoglobin polymer domain may deflect along the z direction due to the heterogeneous growth.…”

The Hb A Variant (β73 Asp→Leu) Disrupts Hb S Polymerization by a Novel Mechanism

“…With a simple model invoking documented polymer bending as well as heterogeneous nucleation, Dou & Ferrone previously showed that the shape of domains begins with a 2-fold symmetry that fans into a spherical shape, referred to as domain closure, after a period of time. 18 If the bending rate is b, then the time for domain closure was found to vary as 1=…”

Dynamic and rheological properties of soft biological cell suspensions

“…To this end, Dou and Ferrone developed a kinetic model for sickle hemoglobin polymerization to understand domain formation. Their qualitative results showed that the transformation of a single fiber into wheat-sheaf bundles and then to spherulitic domains (Dou and Ferrone 1993). Dynamic simulations of self-assembly of sickle hemoglobin confirmed that chain chirality is the main driver for the formation of sickle hemoglobin fibers (Li et al 2012c).…”