交变电磁场对胞浆钙影响机制的研究
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摘要
“电磁污染”越来越引起科学界的关注,近几年来电磁生物效应的研究主要集中在两个方面:流行病学调查和细胞实验研究。在本论文中,以细胞内重要的第二信使钙离子为研究对象,针对单个细胞建立钙离子浓度变化的动力学模型,此模型考虑了细胞的生理特性、膜电位的变化。在此基础上提出了一种新的解释电磁场对整个细胞影响机制的思想。其中我们得出的主要结论为:
(1)在胞内钙振荡“最小”模型的基础上,进行了细胞膜、细胞器膜上各种钙离子蛋白在细胞内钙离子浓度非线性变化中各自敏感性的讨论,得出钙振荡机制中,钙库上的ATP驱动的跨越细胞器膜将钙离子泵入钙库的钙泵是最敏感的区域,这已在相关文献中有所报道,是电磁场最可能的作用位点。
(2)V_m-[Ca~(2+)]_(cyt)模型:·
V_m-[Ca~(2+)]_(cyt)模型考虑了细胞膜上所有与胞浆内钙离子浓度发生改变有关的蛋白。
①解释在交变电场作用下,胞浆膜电位和胞浆内钙离子浓度的变化机制,外部的交变电场会对细胞膜内外的离子施加一种振荡力的作用(F_1=Ezq_e=E_0zq_e sin(2πvt))。当作用力达到某一阈值时,就会介导膜上某种蛋白的打开与关闭,从而影响膜电位的变化,最终达到间接影响各种钙离子蛋白的构象变化,来影响胞浆内钙离子浓度的变化。模拟的结果表明了[Ca~(2+)]_(cyt)的变化和交变电场有一定的关系,当电场强度E_0 (mV/m)与电场频率v(Hz)在数值上比例为1～2时,[Ca~(2+)]_(cyt)的变化最明显。[Ca~(2+)]_(cyt)的生物学反应出现在低频范围内(0～100Hz)。
②交变磁场对每个离子的作用力的大小表示为F_1=Buzq_e=B_0uzq_e sin(2πvt),同样道理,模拟的结果表明了当B_0(G)与v(Hz)在数值上的比率大于4时,[Ca~(2+)]_(cyt)信号出现显著的变化。
(3)V_m-[Ca~(2+)]_(cyt)-[Ca~(2+)]_(ER)模型
V_m-[Ca~(2+)]_(cyt)-[Ca~(2+)]_(ER)模型是包括了细胞膜上所有与胞浆内钙离子浓度发生改变有关的蛋白,以及细胞内钙库上所有与钙离子变化有关的因素。
从模拟结果看,当外加电磁场考虑细胞内钙库时,细胞对电磁场的生物反应范围大大增加了。当电磁场频率、强度增加时,细胞也有相应的反应,这说明电磁场很可能的作用位点存在细胞内钙库上。
另外,本论文还模拟对接了血小板表面的整合蛋白α_(Ⅱb)β_3与RGD小分子。整合蛋白α_(Ⅱb)β_3对血栓的形成具有很重要的调控作用,α_(Ⅱb)β_3与纤维蛋白原上的RGD特征序列结合,促进血小板凝集进而形成血栓。这样可以在理论上设计一个环形RGD小分子(RGD-c)与α_(Ⅱb)β_3蛋白结合,阻断其与纤维蛋白原的结合位点,进而阻断血栓形成。以糖蛋白α_vβ_3(pdb代码1jv2)作为模板,利用modeller8v2软件进行同源模拟得到α_(Ⅱb)β_3三维模型。而小分子则以RGD序列为主,两边各加一个氨基酸X、Y,X和Y之间用一个二硫键相连,通过改变X和Y,重复优化过程则可得到不同的小分子模型,将其与α_(Ⅱb)β_3进行分子对接,可以找出比较理想的XY组合,对治疗血栓的药物设计具有重要的理论指导作用
Interest in hazardous consequences of so-called 'electromagnetic pollution' is increasing within the scientific community. In recent years, researches on biological effects of eletromagnetic filed focus on two aspects: epidemiological investigation and experimental study of cell. In this paper, we take the second messenger calium ion in the cell for the study. The dynamic models on the calcium concentration in the cytosol [Ca~(2+)]_(cyt) was built for single cell. Models include the cellular physiology and changes of the action potential (V_m) of the plasma membrane. A novel thought to explain the mechanism for alternating eletromagnetic filed induced-effects on cytosolic calcium was put forward. The main conclusions were:
(1) The sensitivity of calcium channels on the plasma membrane and calcium stores is discussed for the calcium nonlinear dynamic in the cytosol based on the 'minimal model' about calcium oscillation. The simulated result shows that the ATP-pump on the calcium store is the most sensitive part in the model. This result is consistent with some empirical literatures. The ATP-pump is the possible active part of the eletromagnetic field.
(2) V_m-[Ca~(2+)]_(cyt) model
The V_m-[Ca~(2+)]_(cyt) model includes all channels in the plasma involving in the changes of [Ca~(2+)]_(cyt).
①The mechanism for the alternating electric field induced-effects on V_m and [Ca~(2+)]_(cyt) was elucidated. An alternating external electric field may exert an oscillating force (F_1=Ezq_e=E_0zq_e sin(2πvt)) to each of the free electrolytes, existing on both sides of the plasma membrane. When the force gets to a special value, some membrane proteins will open or close. Thus the changes of the membrane potential will impact the influx and outflux of ions. Consequently, the [Ca~(2+)]_(cyt) changes. The simulated results showed a correlation between the changes of [Ca~(2+)]_(cyt) and the alternating electric field. When the numerical ratio between the intensity E_0 (mV/m) and the frequency v (Hz) of the field was about 1～2, the [Ca~(2+)]_(cyt) signal was changed dramatically. The bioactive changes of [Ca~(2+)]_(cyt) appeared at low frequency, at the range of 0～100Hz.
②An alternating external magnetic field may exert an oscillating force (F_1=Buzq_e=B_0uzq_e sin(2πvt)) to each of the free electrolytes. In the same way, when the numerical ratio between the intensity B_0 (G) and the frequency v (Hz) of the field was about B_0 > 4v, the [Ca~(2+)]_(cyt) signal was changed dramatically.
(3) V_m-[Ca~(2+)]_(cyt)-[Ca~(2+)]_(ER) model
The V_m-[Ca~(2+)]_(cyt)-[Ca~(2+)]_(ER) model includes not only the channels in the plasma membrane, but also the membrane of endoplasmic reticulum (ER).
From the simulated results, we can concluded when the calcium fluxes in the ER is considered, the reaction frequency of the electromagnetic on the [Ca~(2+)]_(cyt) is enlarged dramatically. It proved that the possible active part located on the calcium stores.
Besides the paper have docked integrinα_(Ⅱb)β_3 and the RGD sequence. Integrinα_(Ⅱb)β_3 of the platelet surfaces regulates the thrombosis formation.α_(Ⅱb)β_3 binds to the RGD sequence (Arg-Gly-Asp) of fibrinogen, promotes the platelet aggregation and finally leads to the thrombus. We obtained the three-dimensional molecular structure ofα_(Ⅱb)β_3 using homology-modeling (modeller8v2 software), with integrinα_vβ_3 (pdb code 1JV2) as the template. Accordingly, a cyclic RGD(RGD-c) peptide was designed to bindα_(Ⅱb)β_3 as an antagonist and to block the formation of thrombus. We added two amino acids X, Y to both sides of RGD. X and Y could bind to each other by disulfide bond that finally made RGD-c cyclic peptide. The optimum structure of RGD-c was obtained from the energetic optimization processes. All amino acids were placed at the X and Y to conduct molecular docking to the integrinα_(Ⅱb)β_3 We got the optimum structure of RGD-c by energetic optimization and the antagonistic combination analysis. The results might provide an insight into designing and screening integrinα_(Ⅱb)β_3 antagonists.
(1)在胞内钙振荡“最小”模型的基础上,进行了细胞膜、细胞器膜上各种钙离子蛋白在细胞内钙离子浓度非线性变化中各自敏感性的讨论,得出钙振荡机制中,钙库上的ATP驱动的跨越细胞器膜将钙离子泵入钙库的钙泵是最敏感的区域,这已在相关文献中有所报道,是电磁场最可能的作用位点。
(2)V_m-[Ca~(2+)]_(cyt)模型:·
V_m-[Ca~(2+)]_(cyt)模型考虑了细胞膜上所有与胞浆内钙离子浓度发生改变有关的蛋白。
①解释在交变电场作用下,胞浆膜电位和胞浆内钙离子浓度的变化机制,外部的交变电场会对细胞膜内外的离子施加一种振荡力的作用(F_1=Ezq_e=E_0zq_e sin(2πvt))。当作用力达到某一阈值时,就会介导膜上某种蛋白的打开与关闭,从而影响膜电位的变化,最终达到间接影响各种钙离子蛋白的构象变化,来影响胞浆内钙离子浓度的变化。模拟的结果表明了[Ca~(2+)]_(cyt)的变化和交变电场有一定的关系,当电场强度E_0 (mV/m)与电场频率v(Hz)在数值上比例为1～2时,[Ca~(2+)]_(cyt)的变化最明显。[Ca~(2+)]_(cyt)的生物学反应出现在低频范围内(0～100Hz)。
②交变磁场对每个离子的作用力的大小表示为F_1=Buzq_e=B_0uzq_e sin(2πvt),同样道理,模拟的结果表明了当B_0(G)与v(Hz)在数值上的比率大于4时,[Ca~(2+)]_(cyt)信号出现显著的变化。
(3)V_m-[Ca~(2+)]_(cyt)-[Ca~(2+)]_(ER)模型
V_m-[Ca~(2+)]_(cyt)-[Ca~(2+)]_(ER)模型是包括了细胞膜上所有与胞浆内钙离子浓度发生改变有关的蛋白,以及细胞内钙库上所有与钙离子变化有关的因素。
从模拟结果看,当外加电磁场考虑细胞内钙库时,细胞对电磁场的生物反应范围大大增加了。当电磁场频率、强度增加时,细胞也有相应的反应,这说明电磁场很可能的作用位点存在细胞内钙库上。
另外,本论文还模拟对接了血小板表面的整合蛋白α_(Ⅱb)β_3与RGD小分子。整合蛋白α_(Ⅱb)β_3对血栓的形成具有很重要的调控作用,α_(Ⅱb)β_3与纤维蛋白原上的RGD特征序列结合,促进血小板凝集进而形成血栓。这样可以在理论上设计一个环形RGD小分子(RGD-c)与α_(Ⅱb)β_3蛋白结合,阻断其与纤维蛋白原的结合位点,进而阻断血栓形成。以糖蛋白α_vβ_3(pdb代码1jv2)作为模板,利用modeller8v2软件进行同源模拟得到α_(Ⅱb)β_3三维模型。而小分子则以RGD序列为主,两边各加一个氨基酸X、Y,X和Y之间用一个二硫键相连,通过改变X和Y,重复优化过程则可得到不同的小分子模型,将其与α_(Ⅱb)β_3进行分子对接,可以找出比较理想的XY组合,对治疗血栓的药物设计具有重要的理论指导作用
Interest in hazardous consequences of so-called 'electromagnetic pollution' is increasing within the scientific community. In recent years, researches on biological effects of eletromagnetic filed focus on two aspects: epidemiological investigation and experimental study of cell. In this paper, we take the second messenger calium ion in the cell for the study. The dynamic models on the calcium concentration in the cytosol [Ca~(2+)]_(cyt) was built for single cell. Models include the cellular physiology and changes of the action potential (V_m) of the plasma membrane. A novel thought to explain the mechanism for alternating eletromagnetic filed induced-effects on cytosolic calcium was put forward. The main conclusions were:
(1) The sensitivity of calcium channels on the plasma membrane and calcium stores is discussed for the calcium nonlinear dynamic in the cytosol based on the 'minimal model' about calcium oscillation. The simulated result shows that the ATP-pump on the calcium store is the most sensitive part in the model. This result is consistent with some empirical literatures. The ATP-pump is the possible active part of the eletromagnetic field.
(2) V_m-[Ca~(2+)]_(cyt) model
The V_m-[Ca~(2+)]_(cyt) model includes all channels in the plasma involving in the changes of [Ca~(2+)]_(cyt).
①The mechanism for the alternating electric field induced-effects on V_m and [Ca~(2+)]_(cyt) was elucidated. An alternating external electric field may exert an oscillating force (F_1=Ezq_e=E_0zq_e sin(2πvt)) to each of the free electrolytes, existing on both sides of the plasma membrane. When the force gets to a special value, some membrane proteins will open or close. Thus the changes of the membrane potential will impact the influx and outflux of ions. Consequently, the [Ca~(2+)]_(cyt) changes. The simulated results showed a correlation between the changes of [Ca~(2+)]_(cyt) and the alternating electric field. When the numerical ratio between the intensity E_0 (mV/m) and the frequency v (Hz) of the field was about 1～2, the [Ca~(2+)]_(cyt) signal was changed dramatically. The bioactive changes of [Ca~(2+)]_(cyt) appeared at low frequency, at the range of 0～100Hz.
②An alternating external magnetic field may exert an oscillating force (F_1=Buzq_e=B_0uzq_e sin(2πvt)) to each of the free electrolytes. In the same way, when the numerical ratio between the intensity B_0 (G) and the frequency v (Hz) of the field was about B_0 > 4v, the [Ca~(2+)]_(cyt) signal was changed dramatically.
(3) V_m-[Ca~(2+)]_(cyt)-[Ca~(2+)]_(ER) model
The V_m-[Ca~(2+)]_(cyt)-[Ca~(2+)]_(ER) model includes not only the channels in the plasma membrane, but also the membrane of endoplasmic reticulum (ER).
From the simulated results, we can concluded when the calcium fluxes in the ER is considered, the reaction frequency of the electromagnetic on the [Ca~(2+)]_(cyt) is enlarged dramatically. It proved that the possible active part located on the calcium stores.
Besides the paper have docked integrinα_(Ⅱb)β_3 and the RGD sequence. Integrinα_(Ⅱb)β_3 of the platelet surfaces regulates the thrombosis formation.α_(Ⅱb)β_3 binds to the RGD sequence (Arg-Gly-Asp) of fibrinogen, promotes the platelet aggregation and finally leads to the thrombus. We obtained the three-dimensional molecular structure ofα_(Ⅱb)β_3 using homology-modeling (modeller8v2 software), with integrinα_vβ_3 (pdb code 1JV2) as the template. Accordingly, a cyclic RGD(RGD-c) peptide was designed to bindα_(Ⅱb)β_3 as an antagonist and to block the formation of thrombus. We added two amino acids X, Y to both sides of RGD. X and Y could bind to each other by disulfide bond that finally made RGD-c cyclic peptide. The optimum structure of RGD-c was obtained from the energetic optimization processes. All amino acids were placed at the X and Y to conduct molecular docking to the integrinα_(Ⅱb)β_3 We got the optimum structure of RGD-c by energetic optimization and the antagonistic combination analysis. The results might provide an insight into designing and screening integrinα_(Ⅱb)β_3 antagonists.
引文
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