Molecular Dynamics Simulation On Interaction Of Plasma And Cancer Cell Membranes

Cancer is an important factor threatening human life and health,and the traditional treatment has obvious side effects.In recent years,the clinical application of plasma-assisted cancer treatment has brought new dawn.Cold Atmospheric Plasma(CAP)can be produced in an open environment at room temperature and directly contact with human tissues,and its internal high-density Reactive Oxygen Species(ROS)and Reactive Nitrogen Species(RNS)play an important role in this process,which can ensure the survival of normal cells while selectively apoptotic cancer cells.Relevant experimental studies attributed this mechanism to the specific increase in the concentration of active RONS in cancer cells.However,due to the limitation of experimental diagnostic methods,the microscopic mechanism of the correlation between plasma active particles and cancer cell membranes remains unclear.Based on the classical molecular dynamics method,we simulated the microscopic process of the interaction between CAP and cancer cell membrane to reveal the internal mechanism of selective penetration of plasma RONS through cancer cell membrane.Compared with normal cell membranes,cancer cell membranes have lower cholesterol levels and tend to overexpress aquaporin.Therefore,this paper studied the effect of CAP’s electric field effect on electroporation of cell membrane and the influence of cholesterol content on electroporation effect,and studies the influence of overexpression of Aquaporin(AQP)on the trans-membrane transport of RONS in CAP.The microscopic mechanism of selective penetration of cancer cell membrane by plasma active particles was revealed at atomic level.The main contents of this paper include the following two aspects:(1)To study the effect of CAP’s electric field effect on the membrane structure of cancer cells and the effect of cholesterol content in the membrane on electroporation effect.Under the action of nanosecond pulse electric field,the average perforation time decreases exponentially with the increase of applied electric field intensity.Under the electric field of picosecond pulse,the perforation time also decreases exponentially,but the effect of picosecond pulse is weaker than that of nanosecond pulse.The formation time of electroporation is positively correlated with the pulse frequency,and the lower the frequency,the stronger the effect of electroporation.In order to explain the above trend,the z-axis component of the mean dipole moment of water molecule in the model was analyzed,and the polarization effect of electric field on water molecule was found to be an important factor leading to electroporation of cancer cell membrane.As the pulse frequency increases,the average dipole moment of water molecules under the corresponding electric field decreases,and the polarization of water molecules under the electric field weakens,leading to the decrease of electroporation degree.The effect of cholesterol content in cell membrane on electroporation was studied.With the increase of cholesterol content in the model,the average perforation formation time showed an obvious upward trend,and the electric field threshold of the perforation field showed an approximate linear upward trend,which was consistent with the results of relevant experimental studies.Cancer cell membranes with low cholesterol content are more likely to form electroporation in response to CAP field effects,which facilitates the transport of active RONS across membranes.(2)To investigate the effect of overexpression of aquaporin on the transport of RONS across cancer cell membranes.The transmembrane behaviors of ROS(H2O2,HO2,OH,O2)and RNS(NO,NO2)on pure phospholipid bilayer and AQP1-phospholipid bilayer were simulated.The results of channel radius and water density distribution in AQP1 monomer model are consistent with experimental measurements.Ar/R region and NPA region in monomer channel are the main filtering regions.The distribution of active particles is mainly determined by the number of hydrogen bonds and molecular configuration.Hydrophilic ROS(H2O2,HO2,OH)are mainly distributed in the water layer,and hydrophobic ROS(O2)and RNS(NO,NO2)can achieve concentration accumulation in the phospholipid layer.The addition of AQP1 makes the distribution of the six active particles more in-depth,especially hydrophilic ROS,which can fully contact with ar/R region under the action of hydrogen bond and produce oxidation.Although the oxidation characteristics of H2O2,HO2 and OH slightly affect the monomer channel radius,the infiltration rate is still within a reasonable range.Hydrophilic ROS tend to transmembrane transport through AQP1,while hydrophobic ROS and RNS tend to enter the cell through the phospholipid bilayer.Compared with HO2 and NO2,OH and NO have lower free energy barriers,indicating that these radicals are more likely to enter cells through monomer channels to achieve concentration enhancement.AQP1 overexpressed on cancer cell membranes can significantly improve the transmembrane efficiency of hydrophilic ROS,leading to an increase in the concentration of intracellular active particles.To sum up,this paper studied the microscopic mechanism of selective penetration of CAP active particles through cancer cell membrane and normal cell membrane in terms of cholesterol content and aquaporin expression through classical molecular dynamics simulation.The results showed that the low cholesterol content and overexpression of aquaporin in cancer cell membrane led to selective transport of CAP active particles across the membrane,and ultimately resulted in increased concentration of active particles in cancer cell.This provides a microscopic explanation and theoretical support for the selective inactivation of cancer cells by plasma,which is conducive to the further development of CAP-assisted cancer treatment in clinical treatment.