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Cold atmospheric plasma (CAP) is considered to be a highly promising cancer treatment method, due to its “selective” anti-cancer effect. However, the physical theoretical explanation about this effect and the microscopic interactive mechanisms between CAP and tumors are still lacking. In this work, the CAP-induced electric field-caused electroporation (EP) processes of the cell membrane are modeled based on molecular dynamics. Additionally, the umbrella sampling method is utilized to compute the free energy profile of the intracellular permeation processes of the reactive oxygen species (ROS) through EP-formed pore-like structures at different EP stages. Comparative results are shown as follows. 1) Cancer cell membranes with lower cholesterol components show lower EP-generation threshold and faster EP-formation, and 2) lower free-energy barrier and earlier occurrence of free-energy barrier reduction are shown in all EP stages in cancer cell membrane. The above results explain the difference between cancer cells and normal cells when affected by CAP. Our work delves into the formation of CAP-induced EP and the transport of ROS through EP-formed pore-like structures, which contributes to a better understanding of the microscopic mechanisms of the “selective” anti-cancer effect of CAP, and provides important references for developing CAP-based cancer treatment methods, and devices, thereby facilitating the translation of CAP into clinical applications.
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Keywords:
- cold atmospheric plasma /
- electric field /
- cell membrane electroporation /
- molecular dynamics
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图 1 (a) POPC和胆固醇分子结构; (b) 细胞膜模型示意图. I为液体相, II为POPC头部基团区域, III为POPC尾部区域
Figure 1. (a) Structural components of POPC and cholesterol; (b) schematic diagram of the cell membrane model. I, II, and III represent the liquid phase, the region of POPC head groups and tail groups, respectively.
图 2 不同模型的细胞膜密度分布图, 黑色虚线表示两个POPC层的位置 (a)模型1; (b)模型2; (c)模型3
Figure 2. Density distribution of different cell membrane models: (a) Model 1; (b) Model 2; (c) Model 3. The black dashed lines demarcate the interfacial boundaries of the two POPC molecular layers.
图 3 伞状采样法示意图. 红色虚线表示采样窗口所处的位置
Figure 3. Schematic diagram of umbrella sampling method. The dotted red line indicates the location of the sampling window.
图 4 不同电场强度下细胞膜EP过程示意图. 黑色方框指示出了水突起、水桥和水通道的位置
Figure 4. Schematic diagram of EP processes in cell membrane under different electric field intensities. The black box indicates the location of the water bump, water bridge, and water channel.
图 5 EP进展过程中细胞膜 (a)水分子和(b) POPC分子的z轴总偶极矩. A, B, C分别表示图4中EP的三个阶段
Figure 5. Mean z-axis dipole moment of (a) water molecules and (b) POPC molecules during EP progression. A, B, and C represents the three stages of EP in Figure 4, respectively.
图 6 细胞膜形成EP的时间与电场强度的关系. 括号内分数为: (模拟时间内发生EP的次数)/(总模拟次数)
Figure 6. Relationship between EP formation time and electric field intensity in cell membrane. The score inside the brackets is: (Number of EP occurrences in the simulation time)/(total number of simulations).
图 7 模型1中ROS在EP不同阶段转运的FEP (a)原生细胞膜构象及EP形成过程中的三个阶段构象; (b) H2O2, (c) HO2和(d) OH的FEP
Figure 7. FEP of ROS transport at different stages of EP in Model 1: (a) The conformation of the native cell membrane and the three-stage conformations during the formation of EP; FEP of (b) H2O2, (c) HO2, and (d) OH.
图 8 模型2中ROS在EP不同阶段转运的FEP (a)原生细胞膜构象及EP形成过程中的三个阶段构象; (b) H2O2, (c) HO2和(d) OH的FEP
Figure 8. FEP of ROS transport at different stages of EP in Model 2: (a) The conformation of the native cell membrane and the three-stage conformations during the formation of EP; FEP of (b) H2O2, (c) HO2, and (d) OH.
图 9 模型3中ROS在EP不同阶段转运的FEP (a) 原生细胞膜构象及EP形成过程中的三个阶段构象; (b) H2O2, (c) HO2和(d) OH的FEP
Figure 9. FEP of ROS transport at different stages of EP in Model 3: (a) The conformation of the native cell membrane and the three-stage conformations during the formation of EP; FEP of (b) H2O2, (c) HO2, and (d) OH.
表 1 不同胆固醇含量的细胞膜模型参数
Table 1. Cell membrane model parameters with different cholesterol content.
序号 POPC数量 胆固醇数量 胆固醇含量/% 水分子数 X/nm Y/nm Z/nm 模型1 128 0 0 4873 6.03 6.03 9.07 模型2 112 16 12.5 4705 5.94 5.94 8.25 模型3 102 26 20.3 4513 5.78 5.78 8.39 
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