Molecular Dynamics Simulation Of Cancer Apoptosis Caused By Synergistic Effect Of Reactive Species And Electric Field In Plasma

In recent years,the application of Atmospheric Cold Plasma(CAP)in the treatment of cancer has received extensive attention.Traditional cancer treatment has obvious side effects and is easy to cause serious complications.CAP has been widely used in the study of multiple cancer cell inactivation due to its feature of selectively inactivating cancer cells at room temperature without damaging normal cancer cells.Relevant experimental studies have shown that the synergistic effect of reactive oxygen species(ROS)and reactive nitrogen species(RNS)with local strong electric field in CAP plays a key role in inducing apoptosis of cancer cells.The oxidation effect of Reactive Oxygen and Nitrogen Species(RONS)results in the oxidation of cell membrane lipids.The local strong electric field generated by CAP also leads to the formation of pores in the cell membrane,resulting in decreased selective permeability of the cell membrane.Synergistic effects of the two contribute to RONS entering cancer cells resulting in increased concentrations of reactive species in cancer cells,which in turn oxidationally damage cell structure and induce apoptosis of cancer cells.However,due to the limitations of experimental observation methods,the microscopic process of the above experimental research results is still unclear,and it is urgent to seek new methods to study the microscopic mechanism of plasma-induced apoptosis of cancer cells.In view of the observed phenomena in the experiment,this thesis simulates the membrane penetration process of reactive species under the synergistic action of oxidation effect and electric field based on classical molecular dynamics,and simulates the oxidative damage to cell structure caused by the increase of reactive species concentration in cancer cells based on reactive molecular dynamics to reveal the microscopic mechanism of plasma-induced apoptosis of cancer cells from the molecular level.The main research results are as follows:(1)To explore the effect of lipid oxidation caused by oxidation of reactive species in plasma on the transmembrane transport mechanism of reactive species,cell membrane models containing oxidized phospholipid molecules were constructed,and the transmembrane transport mechanism of RONS under single oxidation effect was studied by classical molecular dynamics simulation.Under the single oxidation effect,the hydrophobic O2 and RNS entering the cell membrane lipid increased,and the permeability efficiency of hydrophobic species increased,especially NO2.Both pure cell membrane and oxidized cell membrane have strong shielding effect on hydrophilic ROS,and simple oxidation effect cannot make hydrophilic ROS overcome hydrogen bond binding and penetrate into the cell membrane.Increasing oxidation ratio has no significant effect on the permeability efficiency of hydrophilic ROS.Only a very small number of HO2 can penetrate the cell membrane at 60%oxidation ratio,and the penetration of hydrophilic ROS requires the assistance of other factors.(2)The effect of electric field synergism on the transmembrane transport mechanism of reactive species in plasma was studied.The electric field was applied to the oxidized cell membrane model.The results showed that the oxidation effect shortened the electroporation time,reduced the electric field intensity threshold of electroporation,and advanced the rise time of Z-axis component of the dipole moment of water molecules.Simulation of the transmembrane process of RONS under the synergistic effect of electric field showed that the synergistic application of electric field caused the phospholipid bilayer to collapse rapidly to form pores,and the formation of electroporation provided a transmembrane channel for hydrophilic ROS.The transmembrane of reactive species in pores is still bound by hydrogen bonding.Hydrophilic ROS tended to be permeable through pores,while hydrophobic O2 and RNS tended to be permeable through phospholipid bilayer membranes.The formation of pores increased the transmembrane efficiency of hydrophilic species while decreased the transmembrane efficiency of hydrophobic species.(3)The microscopic mechanism of oxidative damage caused by reactive species in cancer cells was studied.The effect of OH concentration on the corresponding reaction mechanism was analyzed.The most basic reaction mode of oxidative damage of SDH molecular structure by OH radical is hydrogen abstraction reaction.The degree of hydrogen abstraction reaction varies at different sites according to the activity of chemical bonds,among which S-H bond is the most active,followed by O-H,N-H and C-H bonds.The activity of different amino acids is determined by the type and number of X-H bonds they contain and the nature of the electric charge they carry.The reaction between OH radical and SDH molecular structure leads to the formation of small molecules such as H2O and CO2,the formation of double bonds and X-O chemical bonds in the molecular structure,and the breakage of polypeptide chain skeleton.At low concentration,simple hydrogen abstraction reactions occur between OH and SDH molecules.With the increase of the concentration of OH,the interaction between the unsaturated atoms formed by hydrogen abstraction reactions leads to a series of complex chemical reaction pathways.The reaction efficiency of OH decreases with the increase of the concentration of OH,but the damage effect of low concentration of OH on molecular structure is limited.When considering the dose of plasma,the concentration level of 30～40 can balance the utilization rate of OH radicals and the oxidative damage effect on the molecular structure of SDH.In conclusion,this thesis uses molecular dynamics simulation to study the transmembrane transport mechanism of RONS on cell membranes with impaired barrier function on the one hand,and the intrinsic mechanism of oxidative damage to cell structure in cancer cells after RONS penetrate the membrane on the other hand.The behavior of reactive species in the process of killing cancer cells is completely discussed,and the role of reactive species in the process of inducing apoptosis of cancer cells is revealed from the microscopic level,which provides the microscopic mechanism explanation for the apoptosis of cancer cells by CAP,and promotes the development of CAP in the field of cancer therapy.