Molecular Simulation Of Nanoparticles/Biomolecules Transport Across Lipid Bilayers

Cell membrane is the key interface for the exchange of substances between the inside and outside of the cell.In human body,some small molecules transport across membranes by penetration or specific channels.Some macromolecules and their complexes enter the cell mainly by endocytosis.Similarly,synthetic nanomaterials often enter the cell in either of these ways.An intensive study toward the interface interaction of nanomaterials/biomolecules and cell membrane will not only improve the understanding of some basic life processes,but also provide important guidance for their practical applications in various fields,especially biomedicine.Therefore,in this thesis,the thermodynamic behavior and kinetic process of nanoparticles/biomolecules transport across membranes are investigated by the multi-scale molecular simulation method and Helfrich theory.Moreover,their physicochemical properties and the influence of external environment on the translocation efficiency are studied,and the corresponding physical mechanisms of transmembrane transport under different conditions are revealed,which collectively provides some important theoretical foundations for the experimental design of new nanomaterials.In chapter 1,we introduced the background and related theories of cell membrane.In addition,we also introduced the relationship between cell membrane and nanoparticles/biomolecules,including the research background and transmembrane transport process in vivo.In chapter 2,we introduced the molecular simulation methods for studying the interactions between nanoparticles/biomolecules and cell membranes.Firstly,we described the methods of dissipative particle dynamics and all-atom molecular dynamics,as well as the ideas and theoretical basis of the selection of the force-field parameters in these two methods.Then we introduced the commonly used free energy calculation methods in molecular simulation.Finally,we briefly introduced several molecular simulation software used in this thesis.In chapter 3,we studied the engulfment of nanoparticles by the cell membrane.Based on the improvement of transmembrane transport efficiency of nanoparticles,we accurately regulated its transmembrane capacity.We systematically studied the endocytosis behavior of a nanoparticle complex connected by a polymer chain using dissipative particle dynamics simulations.The results suggested that the nanoparticle complex exhibited the synergistic encapsulation during cell uptake,thus it has a higher uptake efficiency than the single nanoparticle.In addition,we also studied the effect of physical and chemical properties of polymer chains on the uptake efficiency of the nanoparticle complex,and found that the length,rigidity,and hydrophobicity of polymer played an important role in the uptake,while the chemical bond strength of polymer has little effect.More importantly,by adjusting the rigidity of the polymer chain,the nanoparticle complex can be firmly adhered to the surface of the cell membrane,preventing the engulfinent by the cell.Thus,the regulation of different biomedical functions toward nanomaterials was achieved.In chapter 4,we further studied the penetration of nanoparticles through the cell membrane.We systematically studied the physical mechanism of perfluorooctan-/octylmercaptan-modified gold nanoparticles permeating into cell membranes and effects of two nanoparticles on the property of cell membrane through all-atomic molecular dynamics simulations.We found that the type of phospholipids in the membrane and the membrane surface tension had important effects on the permeability of the fluoride gold nanoparticles.By analyzing the surface ligand distribution of the two nanoparticles in water and permeation process,we revealed that fluorinated nanoparticles were amphiphobic(hydrophobic and oleophobic),while alkane-chain-modified nanoparticles are hydrophobic.Finally,we found that the permeability of nanoparticles can be increased by adjusting the degree of fluoridation of the ligands on the surface of nanoparticles.The above results provide some important guidance for the rational design of fluorinated-polymer-modified nanomaterials in biomedical applications.In chapter 5,we studied the penetration related transmembrane transport of biomolecules.Similar to smaller nanoparticles,the penetration mechanisms and physiological toxicity of biomolecules are highly correlated with their structural properties.We investigated the kinetics of bilirabin,a pH-sensitive heterogeneous biomolecule,penetration into cell membrane.Through all-atom molecular dynamics simulation,we systematically investigated the interaction modes of bilirubin with different conformation and cell membrane under different pH conditions.We found that under physiological conditions,Z,Z conformation bilirubin predominates,which is mainly hydrophobic and thus easily embedded into the interior of cell membrane(phospholipid tail region).However,under the condition of external blue light irradiation,bilirubin will change from Z,Z conformation to E,E conformation.The bilirubin at E,E conformation shows a certain hydrophilicity,which greatly reduced its ability to penetrate the cell membrane(especially when they accumulate on the surface of the cell membrane),thus effectively reducing its cytotoxicity.These results provide important theoretical basis for understanding the microcosmic mechanism of bilirubin transmembrane,and for the scientific use of blue light irradiation in bilirubin metabolism and treatment of jaundice.In chapter 6,we summarized the work of this thesis and looked forward to the future work.