Adhesive dynamics simulations of sialyl-Lewisx/E-selectin-mediated rolling in a cell-free system
Adhesive dynamics simulations of sialyl-Lewisx/E-selectin-mediated rolling in a cell-free system
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DOI：
10.1016/s0006-3495(00)76439-3
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发表时间：
2000-10-01
影响因子：
3.4
通讯作者：
Hammer, DA
中科院分区：
文献类型：
--
作者：
Chang, KC;Hammer, DA
选择素介导的白细胞滚动对于免疫应答的正常功能至关重要。最近，在无细胞系统中重新建立了选择素介导的滚动（Biophysical Journal 71：2902-2907（1996））;显示唾液酸刘易斯（x）（sLe（x））涂覆的微球在流体动力学流动下在E-选择素涂覆的表面上滚动。无细胞系统消除了许多混淆的细胞特征，如细胞变形性和信号传导，使我们能够专注于碳水化合物/选择素物理化学在介导滚动中的作用。在本文中，我们使用粘附动力学，一种计算方法，使我们能够模拟粘附，分析在无细胞系统中产生的实验数据。我们模拟的剪切速率，配体密度，和每个粒子的受体数量对滚动速度的影响，并与无细胞系统获得的实验结果进行比较。如果我们假设粒子的人口是均匀的受体密度，我们预测，在模拟中计算的粒子滚动速度是更敏感的剪切速率比实验中发现的。此外，计算出的滚动速度是更敏感的受体的数量的微球比表面上的配体密度，再次与实验相反。我们认为，在整个颗粒人口的受体分布的异质性导致这些差异。我们通过计算受体服从正态分布的种群的平均滚动速度来提高实验和模拟之间的一致性，这表明粒子之间的异质性会显著影响实验结果。理论和实验之间的进一步比较产生0.25埃的sLe（x）/E-选择素相互作用的反应顺应性的估计，接近于文献中报道的E-选择素及其天然配体的反应顺应性（0.3埃）。我们还提供了sLe（x）/E-选择素键形成的内在结合速率的估计值（在10（4）和10（5）s（-1）之间）。
Selectin-mediated leukocyte rolling is crucial for the proper function of the immune response. Recently, selectin-mediated rolling was recreated in a cell-free system (Biophysical Journal 71:2902-2907 (1996)); it was shown that sialyl Lewis(x) (sLe(x))-coated microspheres roll over E-selectin-coated surfaces under hydrodynamic flow. The cell-free system removes many confounding cellular features, such as cell deformability and signaling, allowing us to focus on the role of carbohydrate/selectin physical chemistry in mediating rolling. In this paper, we use adhesive dynamics, a computational method that allows us to simulate adhesion, to analyze the experimental data produced in the cell-free system. We simulate the effects of shear rate, ligand density, and number of receptors per particle on rolling velocity and compare them with experimental results obtained with the cell-free system. If we assume the population of particles is homogeneous in receptor density, we predict that particle rolling velocity calculated in simulations is more sensitive to shear rate than found in experiments. Also, the calculated rolling velocity is more sensitive to the number of receptors on the microspheres than to the ligand density on the surface, again in contrast to experiment. We argue that heterogeneity in the distribution of receptors throughout the particle population causes these discrepancies. We improve the agreement between experiment and simulation by calculating the average rolling velocity of a population whose receptors follow a normal distribution, suggesting heterogeneity among particles significantly affects the experimental results. Further comparison between theory and experiment yields an estimate of the reactive compliance of sLe(x)/E-selectin interactions of 0.25 Angstrom, close to that reported in the literature for E-selectin and its natural ligand (0.3 Angstrom). We also provide an estimate of the value of the intrinsic association rate (between 10(4) and 10(5) s(-1)) for the formation of sLe(x)/E-selectin bonds.