Dynamics Mechanism For Transmembrane Transport Of Nanoparticles

As a natural protection for cells, biomembranes participate in transmembrane transport of materials and maintain the balance of materials between the cell and the environment through endocytosis and exocytosis. So it is very important to investigate the mechanism for transmembrane transport of materials, which play an important role in cell biology and biomedical applications. With the development of computer technology, we can adopt molecular dynamics simulation to investigate a large biological system in a longer time scale. Therefore, in this work we use dissipative particle dynamics simulation to investigate the tranmembrane transport of nanoparticles (NPs). The main contents and innovation are summarized as follows.1 The effect of NP shape for its endocytosis. We investigated detailed endocytosis kinetics for ligand-coated NPs with different shapes, including sphere-, rod-and disk-shaped NPs. Our results indicate that the rotation of NPs is one of the most important mechanisms for endocytosis of NPs with different shapes. Shape anisotropy of NPs divides the whole internalization process into two stages:membrane invagination and NP wrapping. Due to the strong ligand-receptor binding energy, the membrane invagination stage is featured by the rotation of NPs to maximize their contact area with the membrane. While the kinetics of the wrapping stage is mainly dominated by the part of NPs with the largest local mean curvature, at which the membrane is most strongly bent. Therefore, NPs with various shapes display different favorable orientations for the two stages. Our simulation results also demonstrate that the shape anisotropy of NPs can induce an asymmetric and pinocytosis-like endocytosis.2 The effects of NP surface pattern on its penetration across a membrane. Three types of spherical NPs with different surface patterns, including stripy NPs (SNPs), patchy NPs (PNPs) and NPs with random ligand arrangement (RNPs), are considered here. When NPs have the same size and same hydrophilic-hydrophobic ratio, the narrow stripes or small patches as well as RNPs can directly penetrate the cell membrane with a less constrained rotation. For the system with multiple particles sitting on a vesicle, NP aggregation can leads to the shape change of the vesicle. Furthermore, the partial penetration of large SNPs imposes a severe perturbation to the membrane structure, and therefore may cause the leakage of encapsulated solvent or membrane rupture, implying the possible cytotoxicity.3 The effect of NP hardness to its internalization efficiency. Polymeric NP, liposome and solid NP are designed here to represent increasing nanocarrier hardness. Simulation results indicate that rigid NPs can enter cell by a pathway of endocytosis, whereas for soft NP the endocytosis process can be inhibited or frustrated due to the wrapping-induced shape deformation and nonuniform ligand distribution. Instead, soft NPs tend to find penetration pathway to enter the cell membrane via rearranging their hydrophobic and hydrophilic segments.4 The interaction between charged NPs and biomembrane.(1) The self-assembly of patterned charged NPs on biomaterials. By considering the electrostatic distribution of patterned NPs, we investigate the self-assembly of patterned charged NPs, where five surface charged patterns were adopted. It is found that both surface charged pattern and NP size affect the self-assembly of NPs on the cellular membranes significantly. By considering the effects of surface charged pattern and size of the NP on the self-assembly, we found that NP self-assembly needs a minimum effective charged area. When the local charged area of NPs is less than the threshold, its surface charge cannot induce the NP self-assembly, i.e., the surface charged pattern of a NP would determine effectively the self-assembly structure.(2) The effect of membrane potential for NPs adhesion. All cells have an electrical potential across the plasma membrane driven by an ion gradient. We have found that a decrease in membrane potential leads to a decreased cellular binding of anionic NPs. However, the cellular binding of cationic NPs is minimally affected by membrane potential due to the interaction of cationic NPs with cell surface proteins.(3) The internalization of multiple NPs with like charge by a cell. Although there is a repulsive force between neighboring like-charged NPs, their internalization process is found to proceed in a cooperative way, which reflects the competition between the effective membrane-induced inter-NP attraction and the electrostatic repulsion. Moreover, the internalization process depends on the particle size, the charge density on the particle surface, and the initial distance between NPs:Small NPs with like charge are always taken up in a cooperative way; but for the large charged ones, the occurrence of cooperative endocytosis depends on charge density and initial distance.5 The design of a cell-penetrating copolymer (CPC). The inspiration comes from cell-penetrating peptides that have both hydrophilic and hydrophobic residues and are capable of penetrating membranes without inducing membrane disruption. The optimal parameters for the CPC crossing lipid membrane is when the hydrophobic segment length of the CPC is close to the membrane thickness and the CPC has more segment number. Moreover, we found that the penetration mechanism of the CPC is in a zipper way or a cooperative way. By grafting the CPC with the optimal structure on the hydrophilic drug, we found that the CPCs can definitely help the hydrophilic drug penetrate the lipid membrane effectively.6 The mechanism for protein aggregation. Protein as an important building block of membrane plays a significant role in signal transduction and membrane deformation. In this work, we found shape complementarity is the third key factor affecting protein aggregation, besides the electrostatic-complementarity and hydrophobic complementarity. By monitoring different kinds of protein shape-complementarity modes, we gave a clear mechanism to reveal the role of the shape complementarity in the protein-protein interactions, i.e. when the two proteins with shape complementarity approach each other, the conformation of lipid chains between two proteins would be restricted significantly. The lipid molecules tend to leave the gap formed by two proteins to maximize the configuration entropy, and therefore yield an effective entropy-induced protein-protein attraction, which enhances the protein aggregation.