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The Double Nucleation Model for Sickle Cell Haemoglobin Polymerization: Full Integration and Comparison with Experimental Data
Acta Biotheoretica ( IF 1.4 ) Pub Date : 2008-02-05 , DOI: 10.1007/s10441-008-9032-2
Terkia Medkour 1 , Frank Ferrone , Frédéric Galactéros , Patrick Hannaert
Affiliation  

Sickle cell haemoglobin (HbS) polymerization reduces erythrocyte deformability, causing deleterous vaso-occlusions. The double-nucleation model states that polymers grow from HbS aggregates, the nuclei, (i) in solution (homogeneous nucleation), (ii) onto existing polymers (heterogeneous nucleation). When linearized at initial HbS concentration, this model predicts early polymerization and its characteristic delay-time (Ferrone et al. J Mol Biol 183(4):591–610, 611–631, 1985). Addressing its relevance for describing complete polymerization, we constructed the full, non-linearized model (Simulink®, The MathWorks). Here, we compare the simulated outputs to experimental progress curves (n = 6–8 different [HbS], 3–6 mM range, from Ferrone’s group). Within 10% from start, average root mean square (rms) deviation between simulated and experimental curves is 0.04 ± 0.01 (25°C, n = 8; mean ± standard error). Conversely, for complete progress curves, averaged rms is 0.48 ± 0.04. This figure is improved to 0.13 ± 0.01 by adjusting heterogeneous pathway parameters (p < 0.01): the nucleus stability (σ2 μcc: + 40%), and the fraction of polymer surface available for nucleation (ϕ), from 5e−7, (3 mM) to 13 (6 mM). Similar results are obtained at 37°C. We conclude that the physico-chemical description of heterogeneous nucleation warrants refinements in order to capture the whole HbS polymerization process.

中文翻译:

镰状细胞血红蛋白聚合的双成核模型:完全整合并与实验数据进行比较

镰状细胞血红蛋白 (HbS) 聚合会降低红细胞的变形能力,导致有害的血管闭塞。双成核模型表明聚合物从 HbS 聚集体、核中生长,(i) 在溶液中(均相成核),(ii) 到现有聚合物上(异相成核)。当在初始 HbS 浓度下线性化时,该模型预测早期聚合及其特征延迟时间(Ferrone 等人 J Mol Biol 183(4):591–610, 611–631, 1985)。为了解决其与描述完全聚合的相关性,我们构建了完整的非线性模型(Simulink®,The MathWorks)。在这里,我们将模拟输出与实验进展曲线进行比较(n = 6-8 种不同的 [HbS],3-6 mM 范围,来自 Ferrone 的小组)。从开始的 10% 以内,模拟曲线和实验曲线之间的平均均方根 (rms) 偏差为 0.04 ± 0.01(25°C,n = 8;平均值 ± 标准误差)。相反,对于完整的进度曲线,平均 rms 为 0.48 ± 0.04。通过调整异质通路参数 (p < 0.01):核稳定性 (σ2 μcc: + 40%),以及可用于成核的聚合物表面的分数 (φ),从 5e-7,( 3 mM) 至 13 (6 mM)。在 37°C 下获得了类似的结果。我们得出结论,异相成核的物理化学描述需要改进以捕获整个 HbS 聚合过程。01):核稳定性(σ2 μcc:+ 40%),以及可用于成核的聚合物表面的分数(φ),从 5e-7,(3 mM)到 13(6 mM)。在 37°C 下获得了类似的结果。我们得出结论,异相成核的物理化学描述需要改进以捕获整个 HbS 聚合过程。01):核稳定性(σ2 μcc:+ 40%),以及可用于成核的聚合物表面的分数(φ),从 5e-7,(3 mM)到 13(6 mM)。在 37°C 下获得了类似的结果。我们得出结论,异相成核的物理化学描述需要改进以捕获整个 HbS 聚合过程。
更新日期:2008-02-05
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