Molecular Simulations On The Transmembrane Dynamics Of Drug Carriers

In recent years,cancer is becoming a serious threat to human health,which partially results from the.pollution of environment(such as the haze)and the bad behavior of human.A common therapeutic method to treat cancer is the drug therapy.Generally,the carriers that carry drugs are delivered into human body,and transferred into target cell along the body circulation.The drug carriers have many advantages during the therapeutic process,such as weak side effect and less damage to normal cells.The efficient drug delivery and release strongly depend on the properties of carriers,such as the circulation,solubility,targeting and the efficiency of transporting into the biological cell.Therefore,the design and selection of the carriers play an essential role.Both the sphere nanoparticles(NPs)and cell-penetrating peptides(CPPs)have been proved to be efficient in the cell internalization and the high-efficient delivery of drug molecules.However,due to the limitation of the experiment techniques,the microscopic mechanism of how drug carriers cross the biomembrane remains unclear.Molecular simulation is instead an ideal tool to study the microscopic mechanisms and interactions.However the complex of biological membranes and the environment around them in the transmembrane process are often ignored.Therefore,dissipative particle dynamics(DPD)simulation and atomic-molecular dynamics simulation(atomic MD)are applied to study the internalization of NPs and peptides,paying especially attention on the factors that failed to be introduced before.In detail,the cytoskeleton,the osmotic pressure,and the transmembrane potential,the bilayer components and the ionic solution that can influence the transmembrane delivery of these carriers are considered in this thesis.The main contents are given as follows:1.The effect of NP size on its internalization.DPD is applied to investigate the internalization of NPs of different sizes(the diameter of the largest NP reaches to 37.5 nm).Simulation results demonstrate there exist two different wrapping ways:the membrane bending controlled mode and the lipid diffusion dominated mode.The effects of NP size on the internalization depend on the wrapping mode.In detail,when the attraction between the hydrophilic NP and the head group of lipids is weak,the membrane bending energy controls the endocytosis of the NP,which leads more efficient wrapping of large NPs than that of the small NPs.On the contrary,if the attraction between the hydrophilic NP and the head group of lipids is strong,the lipid diffusion becomes obviously and can benefit to the endocytosis of the small NPs.In addition,for the lipid diffusion dominated mode,the rapid endocytosis of the hydrophilic NP with hydrophobic ligands would destroy the membrane and lead to the formation of membrane hole.2.The effect of cytoskeleton under the erythrocyte membrane on the internalization of NP.The DPD simulation results show that the strained skeleton with relative small meshes can inhibite the internalization of NP,depending on the wrapping mode.For the lipid diffusion dominated mode(when the attraction between NP and lipid head group is strong),the NP will be pulled towards the extracellular environment even can be-fully wrapped by membrane.For the membrane bending controlled mode(when the attraction between NP and lipid head group is weak),the inhibition of skeleton to the internalization of NP is reflected by the fact that the NP can only be partially wrapped by membrane.3.The osmotic pressure affects NP internalization and BAR adsorption.DPD is used to study the membrane bleb formation induced by the osmotic pressure difference between two sides of the membrane.The formed membrane bleb can promote both the efficiency of the NP internalization from inside to outside and the aggregation of BAR proteins.In detail,the membrane bleb is formed due to the osmotic pressure across the membrane,which increases the membrane tension.For the endocytosis of hydrophilic NPs on the curved membrane,the wrapping of the NP from inside to outside is faster than that from outside to inside,and the tendency is more obvious for the large NP with weak interaction.For the penetration of hydrophobic NPs,the wrapping rate from inside to outside is slightly larger than that from outside to inside.When there are many hydrophilic NPs,penetration for the NPs occurs at the region around the membrane boundary,while endocytosis take place more frequently at the other region.In addition,the curved BARs tend to adsorb on membrane as forming a path way from ’side’ to ’vertical’.The aggregation of BARs having large intrinsic curvature is found to induce a local membrane curve.The BARs with small curvature that is similar to the membrane can aggregate in ordered structure.4.The influence of transmembrane potential on the direct translocation of cell-penetrating peptides.Based on two-bilayer model and one-bilayer model,we first studied the transmembrane dynamics of peptides under electrical potential by using actomic MD.The results show that the transmembrnae potential can promote the derict penetration of CPPs.On the other hand,the CPPs carrying positive charges will increase the local transmembrane potential.In two-bilayer systems,the transmembrane potential is introduced by adding different ions of positive or negative charge into extracellular and intracellular environment respectively.The simulations show that a high electrical potential will result in a membrane hole in the abcense of the peptides.Furthermore,the absorbed peptides can enhance the local membrane potential and then promote their penetration.In one-bilayer system,we add an external electric field to mimic the transmembrane potential.We found that the free energy required for the penetration of the peptides decreases with the increasing electric field.In addition,combining with the simulation results.and the nucleation theory,the penetration time under normal biology transmembrane potential is caculated and the results are in agreement with the experiment data.5.The interaction between TAT peptides and mixed membrane.Actomic MD is applied tarinvestigate the interaction between HIV-1 TAT peptides and the bilayer.The results show that beside the membrane potential,the negative lipids among the membrane and the adhesive capacity of TATs can also promote the interaction between TATs and membrane.While the excessive ions and the cholesterols will prevent TATs from penetrating.First,using two-bilayer system,we show that in the DPPC bilayer system,the penetration of TATs occurs at high electrical potentials.In the two-bilayer system with POPC/POPG lipids,the negative POPGs prefer to absorb TATs.While adsorption of the peptides and ions will lead to the bending of the membrane instead of forming a membrane pore.In one-bilayer system,the interaction between peptides and POPGs in the absence of excessive ions is much stronger than that in the presence excessive ions.The electrical potential will become larger when more peptides absorb on the membrane.In addition,the stability of the membrane is enhanced by cholesterols,and they prevent the bending of the membrane or the formation of a membrane pore.Besides,fluorescence analysis method was used to detect Bi3+ in aqueous solution.Based on the strong interaction between Bi3+ and hydroxyl and carboxylate groups,porous CAU-1-(OH)2 can detect Bi3+ sensitively and selectively.