Tongtao Yue

Cooperative Effect in Receptor-Mediated Endocytosis of Multiple Nanoparticles

The uptake of nanoparticles (NPs) by a cellular membrane is known to be NP size dependent, but the pathway and kinetics for the endocytosis of multiple NPs still remain ambiguous. With the aid of computer simulation techniques, we show that the internalization of multiple NPs is in fact a cooperative process. The cooperative effect, which in this work is interpreted as a result of membrane curvature mediated NP interaction, is found to depend on NP size, membrane tension, and NP concentration on the membranes. While small NPs generally cluster into a close packed aggregate on the membrane and internalize, as a whole, NPs with intermediate size tend to aggregate into a linear pearl-chain-like arrangement, and large NPs are apt to separate from each other and internalize independently. The cooperative wrapping process is also affected by the size difference between neighboring NPs. Depending on the size difference of neighboring NPs and inter-NP distance, four different internalization pathways, namely, synchronous internalization, asynchronous internalization, pinocytosis-like internalization, and independent internalization, are observed.

Molecular modeling of the relationship between nanoparticle shape anisotropy and endocytosis kinetics

In this work, an N-varied dissipative particle dynamics (DPD) simulation technique is applied to investigate detailed endocytosis kinetics for ligand-coated nanoparticles with different shapes, including sphere-, rod- and disk-shaped nanoparticles. Our results indicate that the rotation of nanoparticles, which is one of the most important mechanisms for endocytosis of shaped nanoparticle, regulates the competition between ligand-receptor binding and membrane deformation. Shape anisotropy of nanoparticles divides the whole internalization process into two stages: membrane invagination and nanoparticle wrapping. Due to the strong ligand-receptor binding energy, the membrane invagination stage is featured by the rotation of nanoparticles to maximize their contact area with the membrane. While the kinetics of the wrapping stage is mainly dominated by the part of nanoparticles with the largest local mean curvature, at which the membrane is most strongly bent. Therefore, nanoparticles with various shapes display different favorable orientations for the two stages, and one or two orientation rearrangement may be required during the endocytosis process. Our simulation results also demonstrate that the shape anisotropy of nanoparticles generates a heterogeneous membrane curvature distribution and might break the symmetry of the internalization pathway, and hence induce an asymmetric endocytosis.

Molecular understanding of receptor-mediated membrane responses to ligand-coated nanoparticles

The cytotoxicity of nanoparticles (NPs) and their potential applications in drug delivery and intracellular imaging have been extensively investigated, and a thorough molecular understanding of how cellular membrane responds to the introduction of NPs is essential for biomaterial design. In this work, N-varied dissipative particle dynamics (DPD) simulation is applied to investigate how a membrane responds to adsorption of ligand-coated NP. Depending on the membrane surface tension, ligand area density and NP size, four kinds of membrane responses are observed: membrane rupture, NP adhesion, NP penetration, and receptor-mediated endocytosis. While endocytosis provides an effective pathway for cellular uptake of NPs, the NP penetration and NP-induced membrane rupture are related to cytotoxicity. These results support the recent experimental reports that NPs have a Janus face for their biomedical applications: serving as carriers for the transmembrane transport of drug and causing cytotoxicity.

The relationship between membrane curvature generation and clustering of anchored proteins: a computer simulation study

The mechanism of biomembrane curvature generation has been studied for decades because of its role in many cellular functions. In this article, N-varied dissipative particle dynamics was used to investigate the relationship between membrane curvature generation and self-assembly of anchored proteins, and a protein aggregation mechanism of curvature generation was proposed. According to the mechanism, the curvature production is enhanced by the self-assembly of proteins, and the enhancement depends on the protein hydrophobic length. Contrary to the theoretic predictions that shallow insertion depth of proteins is more effective in producing positive membrane curvature, our simulations show the opposite trend if the self-assembly of proteins is taken into account. Furthermore, for the membrane proteins with deep insertion, simulations indicate that the self-assembly of proteins may induce membrane vesiculation at negative membrane tensions. In addition, the protein aggregates can sense the membrane curvature, although the way they respond to the local curvature again depends on the protein hydrophobic length. Especially, the self-assembly of shallow inserting proteins is significantly affected by the local membrane curvature.

Molecular modeling of the pathways of vesicle–membrane interaction

In this work we systematically investigate the pathways of the interaction between elastic vesicles and lipid membranes with the aid of computer simulation techniques. Different vesicle responses to the vesicle–membrane adhesion, including vesicle fusion, vesicle hemi-fusion, vesicle adhesion, vesicle endocytosis and vesicle rupture, are observed from our simulations. We also investigate how the pathways of vesicle–membrane interaction depend on the adhesion strength, and the membrane and vesicle properties.

Molecular modeling of interaction between lipid monolayer and graphene nanosheets: implications for pulmonary nanotoxicity and pulmonary drug delivery

Understanding how nanoparticles interact with the pulmonary surfactant monolayer (PSM) is of great importance for safe applications in biomedicine and for evaluation of both health and environment impacts. Here, by performing molecular dynamics simulations, we propose a possible origin of the pulmonary nanotoxicity of graphene-based nanoparticles that comes from a rigidifying effect of graphene nanosheets (GNs) on PSM. This, in reality, indicates that once captured by the PSM, inhaled GNs are hard to be removed from the PSM partially because the expiration or PSM compression is locally restrained, possibly leading to GN accumulation on the PSM. The local rigidifying effect, which is enhanced as multiple GNs approach each other, is found to be dependent on the GN hydrophobicity. In the expiration or PSM compression process, the hydrophilic GN keeps adhering to the monolayer–air interface, while the hydrophobic GN tends to be hosted in the hydrophobic interior and internalize into the PSM via self-rotation. Besides the spontaneous internalization via PSM compression, our pulling simulations indicate that both pulmonary internalization and externalization of GNs can be accomplished by direct translocation across the PSM. The effect of GN hydrophobicity on the direct PSM translocation is well supported by the free energy analysis. This work will help our understanding of pulmonary nanotoxicity of GNs and provide useful guidelines for molecular design of GN-based pulmonary drug delivery materials.

Computer simulation studies on the interactions between nanoparticles and cell membrane

In recent times, nanoparticles (NPs) have received intense attention not only due to their potential applications as a candidate for drug delivery, but also because of their undesirable effects on human health. Although extensive experimental studies have been carried out in literature in order to understand the interaction between NPs and a plasma membrane, much less is known about the molecular details of the interaction mechanisms and pathways. As complimentary tools, coarse grained molecular dynamics (CGMD) and dissipative particle dynamics (DPD) simulations have been extensively used on the interaction mechanism and evolution pathway. In the present review we summarize computer simulation studies on the NP-membrane interaction, which developed over the last few years, and particularly evaluate the results from the DPD technique. Those studies undoubtedly deepen our understanding of the NP-membrane interaction mechanisms and provide a design guideline for new NPs.

Ultrashort Single-Walled Carbon Nanotubes Insert into a Pulmonary Surfactant Monolayer via Self-Rotation: Poration and Mechanical Inhibition

It has been widely accepted that longer single-walled carbon nanotubes (SWCNTs) exhibit higher toxicity by causing severe pneumonia once inhaled, yet relatively little is known regarding the potential toxicity of ultrashort SWCNTs, which are of central importance to the development of suitable vehicles for biomedical applications. Here, by combining coarse-grained molecular dynamics (CGMD), pulling simulations, and scaling analysis, we demonstrate that the inhalation toxicity of ultrashort SWCNTs (1.5 nm < l < 5.5 nm) can be derived from the unique behaviors on interaction with the pulmonary surfactant monolayer (PSM), which is located at the air-water interface of alveoli and forms the frontline of the lung host defense. Molecular dynamics (MD) simulations suggest that ultrashort SWCNTs spontaneously insert into the PSM via fast self-rotation. Further translocation toward the water or air phase involves overcoming a high free-energy barrier, indicating that removal of inhaled ultrashort SWCNTs from the PSM is difficult, possibly leading to the accumulation of SWCNTs in the PSM, with prolonged retention and increased inflammation potentials. Under certain conditions, the inserted SWCNTs are found to open hydrophilic pores in the PSM via a mechanism that mimics that of the antimicrobial peptide. Besides, the mechanical property of the PSM is inhibited by the deposited ultrashort SWCNTs through segregation of the inner lipid molecules from the outer phase. Our results bring to the forefront the concern of the inhalation toxicity of ultrashort SWCNTs and provide guidelines for future design of inhaled nanodrug carriers with minimized side effects.

Interplay Between Nanoparticle Wrapping and Clustering of Inner Anchored Membrane Proteins.

The receptor-mediated endocytosis of nanoparticles (NPs) is known to be size and shape dependent but regulated by membrane properties, like tension, rigidity, and especially membrane proteins. Compared with transmembrane receptors, which directly bind ligands coated on NPs to provide the driving force for passive endocytosis, the hidden role of inner anchored membrane proteins (IAMPs), however, has been grossly neglected. Here, by applying the N-varied dissipative particle dynamics (DPD) techniques, we present the first simulation study on the interplay between wrapping of NPs and clustering of IAMPs. Our results suggest that the wrapping dynamics of NPs can be regulated by clustering of IAMPs, but in a competitive way. In the early stage, the dispersed IAMPs rigidify the membrane and thus restrain NP wrapping by increasing the membrane bending energy. However, once the clustering completes, the rigidifying effect is reduced. Interestingly, the clustering of longer IAMPs can sense NP wrapping. They are found to locate preferentially at the boundary region of NP wrapping. More importantly, the adjacent IAMP clustering produces a late membrane monolayer protrusion, which finally wraps the NP from the top side. Our findings regarding the competitive effects of IAMP clustering on NP wrapping facilitate the molecular understanding of endocytosis and establish fundamental principles for design of NPs for widespread biomedical applications.

Self-assembly of semiflexible homopolymers into helical bundles: a brownian dynamics simulation study.

The controllable self-assembly of semiflexible homopolymers into regular bundles has received much attention because of its potential importance in various fields, such as the storage of elastic energy, the fabrication of nanostructures, and the formation of the cytoskeleton in living cells. In this article, using computer simulations, we investigate how semiflexible homopolymers anchored on a substrate self-organize into ordered structures, focusing on both the patterns formed and the dynamics of self-assembly. For the self-assembly pattern, four different patterns, including patterns with unclustered polymers, disordered semispherical clusters, highly ordered helical bundles, and parallel bundles, are observed from our simulations. The formation of stable bundles requires semiflexible homopolymers having a sufficient molecule length and intermediate bending stiffness, whereas the formation of the helical structures depends on the balance between the inter-homopolymer attraction and the bending stiffness of homopolymers. Furthermore, the bundle formation reinforces the bending stiffness, and the stiffness is further enhanced by the helical bundling. For the dynamic aspect, both hierarchical bundling and nonhierarchical bundling are observed from our simulations.