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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
[1] 卢新培, 罗婧怡, 聂兰兰, 刘大伟, 张冠军, 刘定新, 邵涛, 方志, 金珊珊, 赵亚军, 张远涛, 邹亮, 王晓龙, 李和平, 张宇, 刘东平, 杨德正, 陈支通, 黄青, 程诚, 吴淑群, 刘巧珏, 裴学凯, 闫旭, 程鹤, 熊青, 石琦, 宋珂, 曹颖光, 陈宏翔, 冯爱平, 夏育民, 白帆, 杨春俊, 杨润功, 何光源 2024 高电压技术 50 3555
Lu X P, Luo J Y, Nie L L, Liu D W, Zhang G J, Liu D X, Shao T, Fang Z, Jin S S, Zhao Y J, Zhang Y T, Zou L, Wang X L, Li H P, Zhang Y, Liu D P, Yang D Z, Chen Z T, Huang Q, Chen C, Wu S Q, Liu Q J, Pei X K, Yan X, Cheng H, Xiong Q, Shi Q, Song K, Cao Y G, Chen H X, Feng A P, Xia Y M, Bai F, Yang C J, Yang R G, He G Y 2024 High Voltage Eng. 50 3555
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Yao C G 2018 High Voltage Eng. 44 248
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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, 1 debye =3.335×10–30 C·m
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. 1 debye =3.335×10–30 C·m.
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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[1] 卢新培, 罗婧怡, 聂兰兰, 刘大伟, 张冠军, 刘定新, 邵涛, 方志, 金珊珊, 赵亚军, 张远涛, 邹亮, 王晓龙, 李和平, 张宇, 刘东平, 杨德正, 陈支通, 黄青, 程诚, 吴淑群, 刘巧珏, 裴学凯, 闫旭, 程鹤, 熊青, 石琦, 宋珂, 曹颖光, 陈宏翔, 冯爱平, 夏育民, 白帆, 杨春俊, 杨润功, 何光源 2024 高电压技术 50 3555
Lu X P, Luo J Y, Nie L L, Liu D W, Zhang G J, Liu D X, Shao T, Fang Z, Jin S S, Zhao Y J, Zhang Y T, Zou L, Wang X L, Li H P, Zhang Y, Liu D P, Yang D Z, Chen Z T, Huang Q, Chen C, Wu S Q, Liu Q J, Pei X K, Yan X, Cheng H, Xiong Q, Shi Q, Song K, Cao Y G, Chen H X, Feng A P, Xia Y M, Bai F, Yang C J, Yang R G, He G Y 2024 High Voltage Eng. 50 3555
[2] Chen X, Wang X Q, Zhang B X, Yuan M, Yang S Z 2023 Chin. Phys. B 32 115201
Google Scholar
[3] Fang J L, Zhang Y R, Lu C Z, Gu L L, Xu S F, Guo Y, Shi J J 2024 Chin. Phys. B 33 015201
Google Scholar
[4] Xu H M, Gao J G, Jia P Y, Ran J X, Chen J Y, Li J M 2024 Chin. Phys. B 33 015205
Google Scholar
[5] Schleusser S, Schulz L, Song J, Deichmann H, Griesmann A C, Stang F H, Mailaender P, Kraemer R, Kleemann M, Kisch T 2022 Microcirculation 29 e12754
Google Scholar
[6] Filipic A, Gutierrez-Aguirre I, Primc G, Mozetic M, Dobnik D 2020 Trends Biotechnol. 38 1278
Google Scholar
[7] Nguyen L, Lu P, Boehm D, Bourke P, Gilmore B F, Hickok N J, Freeman T A 2019 Biol. Chem. 400 77
Google Scholar
[8] Zhou R W, Zhang X H, Zong Z C, Li J X, Yang Z B, Liu D P, Yang S Z 2015 Chin. Phys. B 24 085201
Google Scholar
[9] Borges A C, Kostov K G, Pessoa R S, de Abreu G M A, Lima G d M G, Figueira L W, Koga-Ito C Y 2021 Appl. Sci. 11 1975
Google Scholar
[10] von Woedtke T, Laroussi M, Gherardi M 2022 Plasma Sources Sci. Technol. 31 054002
Google Scholar
[11] Min T, Xie X, Ren K, Sun T, Wang H, Dang C, Zhang H 2022 Front. Med. 9 884887
Google Scholar
[12] Yan D, Horkowitz A, Wang Q, Keidar M 2021 Plasma Processes Polym. 18 e2100020
Google Scholar
[13] Yan D, Sherman J H, Keidar M 2017 Oncotarget 8 15977
Google Scholar
[14] 姚陈果 2018 高电压技术 44 248
Yao C G 2018 High Voltage Eng. 44 248
[15] Graves D B 2012 J. Phys. D: Appl. Phys. 45 263001
Google Scholar
[16] Haberl S, Miklavcic D, Sersa G, Frey W, Rubinsky B 2013 IEEE Electr. Insul. Mag. 29 29
Google Scholar
[17] Ruzgys P, Novickij V, Novickij J, Satkauskas S 2019 Bioelectrochemistry 127 87
Google Scholar
[18] Wu E, Nie L, Liu D, Lu X, Ostrikov K 2023 Free Radical Biol. Med. 198 109
Google Scholar
[19] Szlasa W, Kielbik A, Szewczyk A, Rembialkowska N, Novickij V, Tarek M, Saczko J, Kulbacka J 2021 Molecules 26 154
Google Scholar
[20] 孙远昆, 郭良浩, 王凯程, 王少萌, 宫玉彬 2021 物理学报 70 248701
Google Scholar
Sun Y K, Guo L H, Wang K C, Wang S M, Gong Y B 2021 Acta Phys. Sin. 70 248701
Google Scholar
[21] 邢人芳, 陈明, 李芮羽, 李淑倩, 张瑞, 胡笑钏 2024 物理学报 73 188703
Google Scholar
Xing R F, Chen M, Li R Y, Li S Q, Zhang R, Hu X C 2024 Acta Phys. Sin. 73 188703
Google Scholar
[22] Hu X, Jin X, Xing R, Liu Y, Feng Y, Lyu Y, Zhang R 2023 Results Phys. 51 106621
Google Scholar
[23] Yang S, Zhao T, Zou L, Wang X, Zhang Y 2019 Phys. Plasmas 26 083504
Google Scholar
[24] Zhao X, Ding W, Wang H, Wang Y, Liu Y, Li Y, Liu C 2023 J. Chem. Phys. 159 045101
Google Scholar
[25] Bera I, Payghan P V 2019 Curr. Pharm. Des. 25 3339
Google Scholar
[26] Arbeitman C R, Rojas P, Ojeda-May P, Garcia M E 2021 Nat. Commun. 12 5407
Google Scholar
[27] Semmler M L, Bekeschus S, Schäfer M, Bernhardt T, Fischer T, Witzke K, Seebauer C, Rebl H, Grambow E, Vollmar B, Nebe J B, Metelmann H-R, Woedtke T v, Emmert S, Boeckmann L 2020 Cancers 12 269
Google Scholar
[28] Van der Paal J, Neyts E C, Verlackt C C W, Bogaerts A 2016 Chem. Sci. 7 489
Google Scholar
[29] Guo F, Zhou J, Wang J, Qian K, Qu H 2023 Phys. Chem. Chem. Phys. 25 14096
Google Scholar
[30] Bussi G, Donadio D, Parrinello M 2007 J. Chem. Phys. 126 014101
Google Scholar
[31] Parrinello M, Rahman A 1981 J. Appl. Phys. 52 7182
Google Scholar
[32] Hoover W G 1985 Phys. Rev. A 31 1695
Google Scholar
[33] Nose S 1984 Mol. Phys. 52 255
Google Scholar
[34] Hess B, Bekker H, Berendsen H J C, Fraaije J 1997 J. Comput. Chem. 18 1463
Google Scholar
[35] Darden T, York D, Pedersen L 1993 J. Chem. Phys. 98 10089
Google Scholar
[36] Yusupov M, Van der Paal J, Neyts E C, Bogaerts A 2017 BBA-Gen. Subjects 1861 839
Google Scholar
[37] Hu Q, Joshi R P, Schoenbach K H 2005 Phys. Rev. E 72 031902
Google Scholar
[38] Hu Q, Viswanadham S, Joshi R P, Schoenbach K H, Beebe S J, Blackmore P F 2005 Phys. Rev. E 71 031914
Google Scholar
[39] Schmid N, Eichenberger A P, Choutko A, Riniker S, Winger M, Mark A E, van Gunsteren W F 2011 Eur. Biophys. J. Biophys. 40 843
Google Scholar
[40] Cordeiro R M, Yusupov M, Razzokov J, Bogaerts A 2020 J. Phys. Chem. B 124 1082
Google Scholar
[41] Neto A J P, Cordeiro R M 2016 BBA-Biomembranes 1858 2191
Google Scholar
[42] Razzokov J, Yusupov M, Cordeiro R M, Bogaerts A 2018 J. Phys. D: Appl. Phys. 51 365203
Google Scholar
[43] Wu S Q, Dong X, Pei X K, Yue Y F, Lu X P 2017 Trans. Chin. Electrotech. Soc. 32 82 (in Chinse) [吴淑群, 董熙, 裴学凯, 岳远富, 卢新培 2017 电工技术学报 32 82]
Wu S Q, Dong X, Pei X K, Yue Y F, Lu X P 2017 Trans. Chin. Electrotech. Soc. 32 82 (in Chinse)
[44] Nakagawa Y, Ono R, Oda T 2011 J. Appl. Phys. 110 073304
Google Scholar
[45] Verreycken T, van der Horst R M, Baede A H F M, Van Veldhuizen E M, Bruggeman P J 2012 J. Phys. D: Appl. Phys. 45 045205
Google Scholar
[46] Vermeylen S, Waele J D, Vanuytsel S, Backer J D, Van de Paal J, Ramakers M, Leyssens K, Marcq E, Van Audenaerde J, Smiths E L J, Dewilde S, Bogaerts A 2016 Plasma Processes Polym. 13 1195
Google Scholar
[47] Kim S J, Seong M J, Mun J J, Bae J H, Joh H M, Chung T H 2022 Int. J. Mol. Sci. 23 14092
Google Scholar
[48] Geboers B, Scheffer H J, Graybill P M, Ruarus A H, Nieuwenhuizen S, Puijk R S, van den Tol P M, Davalos R V, Rubinsky B, de Gruijl T D, Miklavcic D, Meijerink M R 2020 Radiology 295 254
Google Scholar
[49] Jiang C L, Davalos R V, Bischof J C 2015 IEEE Trans. Biomed. Eng. 62 4
Google Scholar
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