MD/DPD Multiscale Framework for Predicting Morphology and Stresses of Red Blood Cells in Health and Disease.
MD/DPD Multiscale Framework for Predicting Morphology and Stresses of Red Blood Cells in Health and Disease.
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DOI：
10.1371/journal.pcbi.1005173
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发表时间：
2016-10
影响因子：
4.3
通讯作者：
Karniadakis GE
中科院分区：
文献类型：
--
作者：
Chang HY;Li X;Li H;Karniadakis GE
健康的红细胞（RBC）具有显著的变形性，可以挤压直径小至3微米的狭窄毛细血管而不会受到任何损伤。然而，在许多血液疾病中，患病RBC的血影蛋白网络和脂质双层可能显著改变，导致功能受损，包括变形能力丧失。我们采用一个双组分全细胞多尺度模型来量化健康和患病红细胞的生物力学特性，包括恶性疟原虫感染的红细胞（Pf-RBC）和遗传性疾病中有缺陷的红细胞，如球形红细胞增多症和椭圆形红细胞增多症。特别是，我们开发了一个两步多尺度框架的基础上粗粒度分子动力学（CGMD）和耗散粒子动力学（DPD）预测的静态和动态响应的红细胞受到拉伸迫使，仅使用实验信息的结构缺陷的脂质双层，细胞骨架，以及它们之间的相互作用。我们首先采用CGMD上的一个小的红细胞补丁计算剪切模量，弯曲刚度，和网络参数，随后被用作输入到一个全细胞DPD模型来预测红细胞的形状和相应的应力场。对于处于滋养体和滋养体阶段的Pf-RBC，细胞粘附旋钮的存在提高了脂质双层中的剪切响应，并使RBC膜变硬。对于球形红细胞和椭圆形红细胞，双层-细胞骨架相互作用减弱，导致脂质双层中的张应力显著增加。此外，我们还研究了正常和缺陷红细胞的拉伸变形和形状弛豫的瞬态行为。与具有高弹性的正常红细胞不同，我们的模拟表明，缺陷红细胞的反应是不可逆的，即，它们在拉伸和松弛的连续加载循环中失去恢复正常双凹形状的能力。我们的研究结果提供了对红细胞的微观结构和生物力学的基本见解，并证明了本文提出的两步多尺度框架可以有效地用于基于第一原理和蛋白质水平上患者特定实验输入的血液学疾病的计算机模拟研究。红细胞（RBC）及其力学性质在正常和疾病状态下血液的动力学和流变学行为中起着至关重要的作用。然而，红细胞膜性质的精确测定很难在实验上实现。为此，可以使用精确的数值建模来提供用于量化RBC的生物力学性质的有价值的信息。在本文中，我们已经开发并验证了一个两步多尺度框架RBC建模，通过执行分子动力学模拟计算剪切模量，弯曲刚度和网络参数的一个小RBC补丁，然后我们使用作为输入耗散粒子动力学模拟预测应力场和形态缺陷RBC，包括恶性疟原虫感染的RBC以及遗传性球形红细胞增多症和椭圆形红细胞增多症中的RBC。
Healthy red blood cells (RBCs) have remarkable deformability, squeezing through narrow capillaries as small as 3 microns in diameter without any damage. However, in many hematological disorders the spectrin network and lipid bilayer of diseased RBCs may be significantly altered, leading to impaired functionality including loss of deformability. We employ a two-component whole-cell multiscale model to quantify the biomechanical characteristics of the healthy and diseased RBCs, including Plasmodium falciparum-infected RBCs (Pf-RBCs) and defective RBCs in hereditary disorders, such as spherocytosis and elliptocytosis. In particular, we develop a two-step multiscale framework based on coarse-grained molecular dynamics (CGMD) and dissipative particle dynamics (DPD) to predict the static and dynamic responses of RBCs subject to tensile forcing, using experimental information only on the structural defects in the lipid bilayer, cytoskeleton, and their interaction. We first employ CGMD on a small RBC patch to compute the shear modulus, bending stiffness, and network parameters, which are subsequently used as input to a whole-cell DPD model to predict the RBC shape and corresponding stress field. For Pf-RBCs at trophozoite and schizont stages, the presence of cytoadherent knobs elevates the shear response in the lipid bilayer and stiffens the RBC membrane. For RBCs in spherocytosis and elliptocytosis, the bilayer-cytoskeleton interaction is weakened, resulting in substantial increase of the tensile stress in the lipid bilayer. Furthermore, we investigate the transient behavior of stretching deformation and shape relaxation of the normal and defective RBCs. Different from the normal RBCs possessing high elasticity, our simulations reveal that the defective RBCs respond irreversibly, i.e., they lose their ability to recover the normal biconcave shape in successive loading cycles of stretching and relaxation. Our findings provide fundamental insights into the microstructure and biomechanics of RBCs, and demonstrate that the two-step multiscale framework presented here can be used effectively for in silico studies of hematological disorders based on first principles and patient-specific experimental input at the protein level. Red blood cells (RBCs) and their mechanical properties play a crucial role in the dynamic and rheological behavior of blood in normal and disease states. However, the precise determination of RBC membrane properties is hard to be achieved experimentally. To this end, accurate numerical modeling can be used to provide valuable information for quantifying the biomechanical properties of RBCs. In this paper, we have developed and validated a two-step multiscale framework for RBC modeling, by performing molecular dynamics simulations to compute the shear modulus, bending stiffness and network parameters of a small RBC patch, which we then use as input to dissipative particle dynamics simulations to predict the stress field and morphology of defective RBCs, including Plasmodium falciparum-infected RBCs as well as RBCs in hereditary spherocytosis and elliptocytosis.
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DOI：
10.1016/j.cma.2010.02.001
发表时间：
2010-06-01
影响因子：
7.2
作者：
Fedosov DA;Caswell B;Karniadakis GE
通讯作者：
Karniadakis GE
影响因子：
2.4
作者：
Imai, Yohsuke;Nakaaki, Keita;Yamaguchi, Takami
通讯作者：
Yamaguchi, Takami
影响因子：
3.4
作者：
HOCHMUTH, RM;WORTHY, PR;EVANS, EA
通讯作者：
EVANS, EA
影响因子：
3.4
作者：
Butler, James;Mohandas, Narla;Waugh, Richard E.
通讯作者：
Waugh, Richard E.
影响因子：
5
作者：
Diez-Silva M;Dao M;Han J;Lim CT;Suresh S
通讯作者：
Suresh S