Transmembrane Transport Of Functionalized Gold Nanoparticles:a Mesoscopic Coarse-grained Simulation Study

In recent years,gold nanoparticles(AuNPs)with excellent physical and chemical properties have been widely used in many biomedical fields,such as drug delivery,biological detection,optical imaging,photothermal therapy,etc.Usually,the surface of AuNPs are functionalized with different chemical moieties to meet various application requirements.In most of biomedical applications,the AuNPs need to pass through the cell membranes and enter into cells to come into play.It has been demonstrated that endocytosis and direct penetration are two main ways to translocate AuNPs through cell membranes,while the latter may lead to significant toxic effect to the cells.Therefore,exploring the interactions between AuNPs and cell membranes on a molecular level can enable us to get an in-depth understanding of the relevant experimental phenomena,and can also provide theoretical guidance for designing AuNPs with high biocompatibility,low cytotoxicity and specific targeting function.In this dissertation,a mesoscopic coarse-grained simulation method based on the MARTINI force field was adopted to study the interactions between AuNPs with different surface functionalities and lipid membranes,so as to reveal the molecular mechanisms of cellular uptake and potential cytotoxicity and the correlation between them.The major contents and key points of this dissertation are as follows:1.Mesoscopic coarse-grained simulation method was adopted to study the interactions between thiol monolayer-protected AuNPs and lipid bilayers,the factors of surface charge symbol and charge density of AuNPs,the electric charge and structure of bilayers were systematically investigated.The simulation results show that the interactions between AuNPs with different surface electric properties and lipid bilayers exist four different situations,namely,away from the bilayer,adsorption on the bilayer,partially wrapped by the bilayer and penetration into the bilayer.The asymmetric distribution of charged lipids in the membrane is favorable to the penetration of AuNPs.Increasing the surface charge density of AuNPs can improve the penetration efficiency,but also lead to serious bilayer disruption.The penetration of AuNPs with high surface charge density can induce the flip-flop of lipids in the membrane,thus the membrane asymmetry will be destroyed.It has been demonstrated that the formed hydrophobic contacts between the hydrophobic ligands and the protruding solvent-exposed lipid tails mediate the insertion of AuNPs with low surface charge density,while the electrostatic interactions govern the permeation of AuNPs with high surface charge density in the membranes.The results of this work can well explain some related experimental phenomenon,and would help people better understand the interactions between AuNPs and cell membranes at molecular level.2.On the basis of the previous chapter,we further studied the interactions between thiol monolayer-protected AuNPs with different surface electric properties and lipid vesicles.The simulation results indicate that AuNPs can penetrate more easily into the vesicle membranes when compared with the planar lipid membranes.The reason is that the increased surface tension of curved vesicle membranes could lead to the loose arrangement of lipids in the membrane,thus providing great convenience for the penetration of AuNPs.The surface charge symbol and charge density of AuNPs can significantly influence their interactions with lipid vesicles,and different interaction modes are observed.With the increase of surface charge density,the interaction modes between positive AuNPs and lipid vesicles are insertion,partial penetration and total penetration,respectively,which the total penetration is mediated by a continuous hydrophilic nano-hole formed on the vesicle.However,for negative AuNPs,three interaction modes,namely,partial insertion,weak adsorption and repulsion,are observed.In general,the membrane curvature can facilitate the cellular uptake of AuNPs.This work can further enrich the understanding of interactions between AuNPs and cell membranes.3.The interactions between cell-penetrating peptide(CPP)TAT and conjugated AuNPs with lipid bilayers are explored by mesoscopic coarse-grained simulation method.It shows that TAT peptide cannot spontaneously penetrate through the membrane at low concentrations,because a big energy barrier must be overcome.Increasing the peptide concentration can increase the average translocation number of TAT peptide,but will also lead to more serious membrane disruption.The transmembrane mechanism of TAT peptide has little correlation with the cooperative effect between peptides,it mainly due to the global thinning of membrane thick after the peptides are adsorbed on the bilayer surface.When the peptide concentration exceeds a critical value,a hydrophilic nano-hole will appear on the membrane surface,then the TAT peptides cross the membrane through the formed hole one by one.After decorating a certain amount of TAT peptides on the surface of AuNPs,the formed complexes can translocate across the bilayer by inducing a hydrophilic membrane hole,the AuNP doesn't stay in the membrane core,indicating the TAT peptide can facilitate the translocation of AuNPs.This work reveals the transmembrane mechanism of TAT peptide at the molecular level,it can be helpful in both further recognizing the transporting ability of the CPPs and the design of nanocarriers in drug delivery.4.The interactions between pH-responsive zwitterionic polymer-modified AuNPs(Zwitt-AuNPs)and lipid bilayers were studied by using mesoscopic coarse-grained simulation method,the AuNPs coated with poly(ethylene glycol)(PEG-AuNPs)used as a comparison.Simulation results show that the Zwitt-AuNPs can more easily approach the membrane surface.There are different interaction modes between the Zwitt-AuNPs and the bilayer under different protonation degrees.When the protonation degree is low,the Zwitt-AuNPs adsorb on the bilayer;when the protonation degree is moderate,the Zwitt-AuNPs can translocate across the bilayer through a hydrophilic membrane hole-mediated pathway;when the protonation degree is high,the Zwitt-AuNPs will be fully wrapped by the curved bilayer.An interesting interplay between the chain length and the protonation degree of polymers on the interactions between the Zwitt-AuNPs and lipid bilayers.The increase of polymer chain length will suppress the translocation of Zwitt-AuNPs at low protonation degree,while it can enhance the transmembrane efficiency of AuNPs at high protonation degree.This work reveals the molecular mechanism of the interactions between the Zwitt-AuNPs and cell membranes under different pH conditions,which can provide theoretical guidance for the design and fabrication of pH-responsive nanocarriers based on zwitterionic materials.