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SCIENCE CHINA Chemistry • REVIEWS • · SPECIAL TOPIC · Biophysical Chemistry

December 2014

Vol.57 No.12: 1662–1671

doi: 10.1007/s11426-014-5231-7

Computer simulation studies on the interactions between nanoparticles and cell membrane TIAN FaLin1, YUE TongTao2, LI Ye1 & ZHANG XianRen1* 1

State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, China 2 State Key laboratory of Heavy Oil Processing, Center for Bioengineering and Biotechnology, China University of Petroleum (East China), Qingdao, 266555, China Received July 9, 2014; accepted July 21, 2014; published online November 4, 2014

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. dissipative particle dynamics, coarse grained molecular dynamics, membrane-nanoparticle interaction, endocytosis, penetration

1 Introduction With the rapid development of nanotechnology, the nanoparticles (NPs) have nowadays received intense interest due to their potential applications in diagnostics and therapeutics [1–16]. Though this technology provides a new route to use NP as a transport tool for drug delivery, however, it poses the potential undesirable effects, including the negative impacts on human health, namely, nanotoxicology [17–29]. As a basic unit of life, cells in multicellular organisms contain fundamental molecules of life and carry out most of organism functions. The cell membrane, which is the interface between the cell and the surrounding environment, not

*Corresponding author (email: [email protected]) © Science China Press and Springer-Verlag Berlin Heidelberg 2014

only protects the wholeness of the cell, but also participates a number of bioprocesses, such as communication among cells [30, 31] and uptake of nutrients [11, 13, 32]. As the first step to the biomedicine and nanotoxicity, it is crucial to understand the interaction between cell membrane and NPs [33, 34]. In recent years, numerous studies have been performed on the interaction between the NPs and the cell membrane through in vivo and in vitro experiments [5, 35–37], theoretical analysis [38–41] and the computer simulations [42–50]. Several mechanisms for the NP-membrane interaction have been proposed. All of these studies fall into two broad categories: the NP toxicity and the internalization pathways of NPs [51–53], both of which are found to be affected by several factors, like NP size [35, 45, 53–62], geometrical shape and surface modification of NPs [7, 12, 34, 47, 49, 54, 60, 63–75], and the surrounding environment chem.scichina.com

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[14, 76]. For example, from the experimental aspect, a number of studies concentrated on the effects of NP size have appeared. Mou et al. [59] recently used confocal laser scanning microscopy (CLSM) to find that the cellular uptake of the monodisperse mesoporous silica nanoparticle (MSN) depend on the NP size. They showed that NPs having a size of 170, 110, 50, and 30 nm can be internalized into cells, but cannot penetrate the nucleus. More interestingly, it is demonstrated that cellular uptake is highly particle-sizedependent in the order of 50 nm > 30 nm > 110 nm > 280 nm > 170 nm. The uptake efficiency for 50 nm NPs is approximately 2.5 times as high as that of 30 nm NPs, 4 times higher than that of 110 nm particles, 20 times higher than that of 170 nm particles, and 11 times higher than that of 280 nm particles. A similar particle size dependence was also presented by Osaki et al. [61] and Jiang et al. [35]. Beside the influence of the NP size, the cellular uptake of NPs also depends on NP concentration in the solution. It is demonstrated that there exist a threshold concentration for NP internalization, above which the uptake increases with the NP concentration. In addition to above studies, there also exist numerous experimental studies on the interaction between the plasma membrane and the NPs [2, 70, 77–85]. Although extensive experimental studies have been carried out in literature in order to understand the NPmembrane interaction, very scanty is known about the kinetic evolution of the interaction process. In addition, in most cases experimental observation fails to provide accurate molecular details of the interaction mechanism. Therefore, it would certainly be desirable to examine the molecular mechanism for the NP-membrane interaction. Such examination is readily possible now. In most case it is now feasible to simulate one or several small proteins or bio-molecules interacting with lipid bilayer, in water by using all-atom force field. However, it is difficult to include NPs and cell membrane in all-atom simulations because the length scale is about tens of nanometers (several million atoms) and the time scale is at least 10 ns (several billion time steps), which is far beyond the present computing ability. Instead, coarse grained molecular dynamics (CGMD) and dissipative particle dynamics (DPD) simulations have often been used to investigate the interaction mechanism as well as the corresponding interaction pathway. For example, it is indicated experimentally that when the cells (like lung epithelial cells and macrophages) are exposed to a solution of graphene, a kind of NPs with a strong shape anisotropy, the graphene would penetrate into the cell membrane [86]. To understand how the penetration of graphene nanoparticle enters the cell, Gao et al. [86] performed computer simulations, and they showed that graphene would enter cells through spontaneous penetration at edge or corner sites. Above examples undoubtedly indicate the ability of computer simulation techniques in investigation of the NP-membrane interaction. This is also the reason why nu-

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merous computer simulation studies have been performed recently. In the present review, recent computer simulation studies on the interaction between the plasma membrane and NPs are summarized, in particularly we stress the results from the dissipative particle dynamics (DPD) technique [87–94].

2 DPD simulation technique The DPD method, which allows the simulation being carried out over a millisecond time scale and micrometer length scale, was first introduced to simulate the hydrodynamic behavior of complex fluids [44, 95]. Especially, this method was proved to be especially useful in studying the mesoscale behaviors of lipid bilayer membranes [87, 94, 96]. The elementary units of DPD simulations are soft beads whose dynamics are governed by the Newton’s equation of motion, similar to that in the molecular dynamics method. For a particle i, each DPD bead is subjected to three types of forces: conservative forces ( FijC ), dissipative forces ( FijD ), and random forces ( FijR ), namely,

 (F j i

C ij

fi 

 F  F ) . The conservative force between beads D ij

R ij

i and j , which is soft repulsive, is determined by  rij  1  aij (1  rij )rij C , where aij is the maxiFij   rij  1 0 mum repulsive strength, rij  ri  rj ( ri and rj are the posi tions of beads i and j ), rij  rij , rij  rij / rij and rc is the

interaction range. The other two forces FijD and FijR are simultaneously responsible for the conservation of total momentum in the system, and they incorporate the effect of Brownian motion into the larger length scale. The DPD method has been proven to be efficient in investigation of the dynamics of soft matter at the mesoscopic level, for example, colloidal crystallization of gold nanoparticles [97], internalization of the nanoparticles [49, 98, 99], membrane reshape of the cell, and polymer-brush bilayers with colloidal inclusions [100]. Figure 1(a–c) illustrates a typical coarse grained model for different components in DPD simulations [99]. In the model, each dipalmitoylphosphatidylcholine (DPPC) molecule is built by thirteen DPD beads that contain a head-group with three hydrophilic beads (H) and two hydrophobic tails having five hydrophobic beads (T). The interaction between neighboring beads along the same lipid molecule is described by a harmonic  spring force, FS  K S (rij  req )rij where K S and req are

the spring constant and the equilibrium bond length respectively. The force constraining the variation of bond angle is given by F  U and U   K (1  cos(  0 )) , where

0 was normally set to  and K is the bond bending force

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constant. A spherical solid nanoparticle (NP), which is coated by the ligands, has constrained mobility as a rigid body (Figure 1). Solvent molecules and other beads are not allowed to enter the interior of the nanoparticle.

3 NP properties affect the NP-membrane interaction Plasma membrane normally consists of different type of phospholipids and membrane proteins [31, 101–104]. To maintain the cell integrity, the cell membrane must be impermeable to most macromolecules and NPs. Adsorption of NPs influences the membrane in several ways. First, the adsorbed NPs may alter the properties of the plasma membrane, such as the bending elasticity, the membrane tension and the diffusion coefficient of lipids on the membrane [56, 105–110]. Second, the adsorption of NPs can induce the phase change of the multiple-component membrane. For example, the charged NPs may trigger the phase separation


when they interact strongly with a special type of lipids having opposite charges, and this phase separation would affect the signal transmission between cells. Finally, the addition of NPs probably changes the morphology of cell membrane [73, 111] and induces different membrane responses. Depending on the properties of NPs and membrane, different forms of NP-membrane interaction are found, including NP adhesion on the membrane, NP aggregate on the membrane, NP encapsulation inside the membrane, NP penetration (translocation) across the membrane, NP endocytosis, membrane rupture and the formation of membrane holes. The aforementioned factors, which influence the interaction between the NPs and the membrane, can be divided into different categories: the (physical and chemical) properties of NPs and those for membrane. The effects of these factors are subsequently discussed below. We first discuss that how the NP properties affect the NP-membrane interaction. With the rapid development of synthesis techniques, NPs

Figure 1 Different components of the DPD simulation (a–c) and four kinds of membrane responses to adsorption of NPs (d–g). (a) Lipid molecule; (b) transmembrane receptor; (c) ligand-coated NP; (d) receptor-mediated endocytosis; (e) adhesion of the NP on membrane surface; (f) penetration of the NP into membrane; (g) NP-induced membrane rupture. Reproduced from Ref. [99].

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featured with various properties have been reported. At present, the effects of following NP properties on their interaction with cell membrane have been considered which are: NP size, NP shape, NP hydrophilicity, NP dose (concentration), surface coating and especially surface charge. Sometimes, one of these properties dominates the interaction between the NPs and the membrane, but more frequently, there exist several properties that collectively determine the interaction.

NP-membrane system into two parts: the bending energy of the membrane and the adhesion energy between NPs and the membrane. The bending energy of the membrane is influenced by NP radius when NPs are wrapped by the membrane. To minimize the total free energy of the NPmembrane system one can theoretically obtain the relation between the NP radius and the wrapped membrane.

3.1 NP size

Besides the size, the shape of NPs is another important intrinsic property affecting the NP-membrane interaction, as demonstrated both experimentally and theoretically. For example, some kinds of NPs with a high aspect ratio, like carbon nanotubes and asbestos fibres, have been shown to cause length-dependent toxicity in certain cells. To understand how NPs with a high aspect ratio interact with a plasma membrane, Gao et al. [116, 117] performed both experimental and theoretical studies, and found that NPs with high aspect ratio (like carbon nanotube) first enter cells through the tip. It is the tip-first mechanism that leads to near-vertical entry of carbon nanotubes with end caps and prevents the long NPs from entering cell completely. However, nanotubes without caps on their tip show a different mechanism for NP uptake. This conclusion is similar to that reported by Vácha et al. [74] where passive endocytosis (i.e., not ATP driven) has been found to depend on the shape of the NPs. In their studies, CGMD simulation results confirmed that the efficiency of the passive endocytosis is higher for the spherocylindrical particles than for the spherical ones with same diameter [74]. The NP shape influences not only the efficiency of cellular uptake but also the uptake pathway. For NPs with different shapes, Yang and Ma [49] showed that the shape anisotropy and initial orientation of the NPs dominate the process for NP translocation across the lipid bilayer. Li et al. [73] performed DPD simulations to show the rotation of NPs, which was found to be one of the most important mechanisms for endocytosis of the shaped NP that regulates the competition between ligand-receptor binding and membrane deformation. As a result, the whole internalization process for those non-spherical NPs can be divided into two stages: membrane invagination and NP wrapping [73]. Furthermore, they demonstrated that NPs having various shapes show different favorable orientations at the two stages.

NP size is one of the most important parameters in designing suitable cell tracking and drug delivery systems. Additionally, it often determines the mechanism and rate of cellular uptake of NPs. Many experimental and computer simulation studies have been recently reported from the field of cellular uptake of NPs, and it has been found that particle size can affect the efficiency and pathway of cellular uptake. Furthermore, several mechanisms have been proposed that relate NP size to the extent of membrane disruption and to the structure of NP-lipid assemblies. Using DPD simulation technique, Yue and Zhang [99] found that small NPs (R < 3.0 nm) can penetrate the membrane directly or just adhere on the membrane surface, sometimes followed by membrane rupture (the formation of membrane pore); while for large NPs, they are often partly encapsulated by the membrane or internalized via pathways such as ‘phagocytosis’ and ‘pinocytosis’ (Figure 1). Similarly, Lin et al. [45] performed CGMD simulations to investigate the size effect for hydrophobic NPs across the dipalmitoylphos-phatidylcholine (DPPC) bilayer. The authors also found that different NP sizes have different effects on the structural change of membrane. The same size effect was showed experimentally by Roiter et al. [112], although the critical NP size obtained for the change of interaction pathways is different from that of computer simulations [99]. Using AFM they studied the interaction of L-R-dimyristoyl phosphatidylcholine (DMPC) with silica NPs having a size ranging from 1 to 140 nm. After analyzing a series of the AFM images, they found that small NPs (R < 22 nm) would induce a hole in the lipid bilayer, whereas larger NPs are mostly covered with the lipid bilayer as a whole [112]. In addition to studies related to the interaction between hydrophilic NPs and a plasma membrane, others have also reported it to be thermodynamically favorable especially in case of hydrophobic NPs with size of R = 2–8 nm that are embedded within a lipid bilayer [48]. This indicates that it may be possible for the membrane to embed NPs having a diameter in proximity to, or even exceeding the membrane thickness. The size effect was often interpreted theoretically with Helfrich elastic model [41, 45, 47, 106, 113–115]. The Helfrich model decomposes the total free energy of the

3.2 NP shape

3.3 NP hydrophilicity and surface modification Numerous studies demonstrate that addition of NPs often induce the morphological reorganization of cell membrane and the formation of membrane hole, strongly depending on the surface modification of the interacting NPs [34, 39, 54, 57, 63–66, 68, 70, 75, 84, 118]. Moreover, it is found that the cellular uptake of the hydrophilic NPs and that for hydrophobic NPs have different mechanisms and pathways.

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Computer simulations show that the surface hydrophobicity of NP can induce different internalization mechanisms in NP-membrane systems. To understand the effect of the surface ligands on the interaction between the surface ligand-coated NPs and the lipid bilayer, Yue and Zhang [99] used DPD simulations and revealed the existence of four possible kinds of membrane responses to the ligand-coated NPs (Figure 1(d–g)); NP induced membrane rupture, NP adhesion to the membrane surface, NP penetration into the membrane, and receptor-mediated endocytosis. All of these four responses are controlled by NP properties and those of membrane, like NP size, membrane tensions and ligand density on NP surface; especially, both the density and distribution of the ligands on the NP surface are crucial for the membrane response to NP adsorption [99]. Li et al. [119] performed CGMD simulations to investigate the effect of hydrophilic/hydrophobic properties of NPs on their interaction with DPPC membrane. Simulation results show that hydrophobic NPs could result in their inclusion into the membrane, while hydrophilic NPs are just absorbed on the membrane surface. In contrast to the homogeneous surface modified NPs, Ding et al. [120] investigated the interaction between Janus NPs and membrane, and found that there exist two different late-stage states for the Janus particle-membrane system: insertion and engulfment. During the insertion state, the hydrophobic part of NPs is inserted into the interior of the lipid bilayer, while the hydrophilic part stays outside the membrane. However, during the engulfment state, the hydrophilic part is engulfed by lipid heads by receptor-ligand interaction and the hydrophobic part is “engulfed” by lipid tails with hydrophobic interaction. The difference between the two late-stage states is controlled by the initial orientation and the properties of the Janus NPs [120]. To gain insight into the effect of the surface properties of the ligand-coated NPs, Li et al. [67] performed DPD simulations showing evolution of free energy when NPs with different ligand patterns cross a lipid bilayer. In their studies, four kinds of ligand patterns were considered; NPs modified as stripe-like structure with alternating hydrophilic and hydrophobic ligands, NPs modified with randomly mixed ligands at the same hydrophobic and hydrophilic ligands, as well as NPs coated solely with homogeneous hydrophobic or hydrophilic ligands. The free energy analysis indicates that the stripe-like NPs encounter the lowest energy barrier when translocated across the lipid membrane. This is because the stripy NPs tend to rotate to a preferred orientation and remain in the same orientation as they penetrate the bilayer. Except the chemical properties of the coating ligands on the NP surface, the physical properties of the coating ligands on the NP surface also have important impacts on the receptor-mediated endocytosis of nanoparticles. Ding and Ma [121] used DPD simulations to show that the ligand density and length as well as its rigidity can strongly affect


the final equilibrium in the receptor-mediated endocytosis. More interestingly, it was found that the particle decorated with longer ligands is more likely to attach to the membrane, though it is harder to be totally engulfed. Increasing the ligand density on the surface of the NP and rigidity which enhances the uniform distribution of ligands on the particle may lead to the complete engulfment [121]. 3.4 Surface charge of NPs This transmembrane potential, which is induced by the difference between cytosolic and extracellular potassium concentrations, could affect the interaction between the NPs and the membrane, especially by influencing the charged NPs that interact with the polar membrane [57, 63–66, 122–130]. To investigate the influence of surface charges, Shin et al. [131] combined experimental and computer simulation techniques to confirm that the decrease of membrane potential leads to decreased cellular binding of the anionic NPs. They also demonstrated that the increase of membrane potential reverses this trend and results in increased binding of anionic NPs. However, the cellular binding of the cationic NPs is minimally influenced by the membrane potential, but dominated by the interaction between the cationic NPs and the membrane proteins [130]. This study indicates that membrane potential is an important factor that must be considered in the designing of NPs for therapeutic and sensing applications. Similarly, Li and Gu [132] performed CGMD simulations and show that compared to the uncharged NPs, charges on NP surfaces improves their adhesion to the membrane due to the electrostatic attraction. Moreover, NPs with negative charges often induce the formation of the high ordered region in fluid bilayers [131]. Therefore, the adsorption of cationic/anionic NPs on the membrane plays different roles in suppressing or promoting the membrane wrapping. The distribution of charges on the NP surface also affects the binding of NPs to a lipid bilayer, and thus may induce effective NP-NP interaction. With DPD simulations Li et al. [126] demonstrated the importance of the pattern of surface charges and showed that the different charge patterns may induce different morphologies of NP aggregates on membrane. The authors also pointed out that the aggregation of charged NPs requires a minimum effective charged area, above which the pattern of the electrostatic distribution determines the arrangement of self-assembled NPs. Another study pointed out that cationic gold NPs (AuNPs) are more disruptive to negatively charged lipid membrane, often leading to the formation of the transient membrane holes [133]. The formation of membrane pores depends on the number of positive charges on the NP surface. Likewise, positively charged NPs can also induce flipping of membrane areas, leading to particle inclusion and membrane depolarization [63].

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3.5 NP concentration As mentioned above, the interaction between a single NP and a plasma membrane is controlled by NP size, NP shape, and the surface physical and chemical properties of the NP. However, in real systems the membrane often interacts with multiple NPs simultaneously [2, 5, 7, 9, 13, 134, 135], and NP cytotoxocity is sometimes found only at high NP concentrations. From a systematical investigation on the adsorbed semihydrophobic NPs on the supported lipid bilayers (SLBs), Jing and Zhu [134] pointed out that there exists a critical NP concentration for NPs having different degree of surface hydrophobicity, above which the SLBs will disrupt. Consistently, Lipowsky et al. [136] found that the mechanism for the interaction between multiple NPs and the membrane is different from that for the single NP interacting with the membrane. Through DPD simulations Yue and Zhang [137] indicated that the internalization of the multiple NPs was in fact a collective phenomenon. There exists an effective attraction between two neighboring NPs, which is mediated by the curvature of the membrane. It is this attraction that induces cooperative endocytosis of multiple NPs on the whole. Further simulations indicated that this membrane curvature mediated interaction was controlled by the inter-NP distance, or equivalently, the dose of the NPs. Similarly, Chen et al. [98] performed DPD simulations to show that the NP concentration has an important effect on the interaction between the NPs and the lipid vesicle. The small NPs with a


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radius less than 2.0 nm, adhere on the surface of the vesicle at low NP concentrations. With the increase of the NP concentration, these penetrate into the vesicle. By further increasing the NP concentration to a threshold value, the vesicle will rupture. More interestingly, three different pathways for spontaneous NP penetration were identified; depending on NP size and NP concentration (Figure 2). In general, NP properties play a crucial role in the interaction between NPs and plasma membrane. Understanding the effect of these factors will promote the biological application of the NPs more effectively in the future. Simulation results show that in some cases, one of the NP properties would dominate the NP-membrane interaction, but more frequently, it is several of them that cumulatively determine the interaction.

4 The effect of the membrane properties to the NP-membrane interaction Similar to the properties of NPs that affect the NP-membrane interaction, the properties of plasma membrane also show significant influences on the NP-membrane interaction. Among various membrane properties, the effects of membrane tension and membrane composition have been extensively studied. Various bioprocesses taking place on cell membrane may change the membrane tension frequently and sometimes locally [31, 62, 68, 73, 99, 126, 137, 138], which would in turn alter the NP-membrane interaction. Considering this,

Figure 2 Three different pathways for NP penetrations. (a) Cooperative chain-like penetration; (b) direct penetration; (c) inverted micelle-like penetration. The arrows indicate the positions of NP penetration. Reproduced from Ref. [98].

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Yue et al. [31, 50, 99, 137] used N-varied DPD simulations to demonstrate that the membrane tension significantly affects the NP-membrane interaction. When the membrane tension is sufficiently positive, the perturbation induced by NP adsorption may rupture the membrane. At a mild membrane tension, NP adhesion or penetration is observed, that depends on the strength of NP-membrane adhesion. However, when the membrane tension decreases to a negative value, the NPs will be internalized by the cell membrane via a pathway of endocytosis [127]. Using computer simulations and theoretical analysis, Guo et al. [139] also confirmed that the membrane tension plays a significant role for wapping dendrimer-like NPs. They found that when the membrane tension is larger than a critical value, the dendrimer would induce membrane disruption. Otherwise, depending on the membrane tension three states for the NP-membrane system, including the dendrimer penetration, partial wrapping and full wrapping, were found [98]. Beside the NP properties and membrane tension, there exist other factors that affect the NP-membane interaction. For example, membrane proteins have been found to have remarkable influence on the interaction between the NPs and the membrane [140–144]. Many of membrane proteins have been reported which take part in the endocytosis process. It is well known that specific cell-surface receptors and Rho- family GTPases are required for the facilitating different phagocytic processes [145]. Note that in most situations membrane proteins not only participate in the NP-membrane interaction, but also change the membrane properties. For instance, Yue et al. [31] and Li et al. [88–91] found that the self-assembly of the anchored proteins can induce membrane curvature. Temperature is another factor affecting the NPmembrane interaction; and in general high temperature would increase the fluidity of the membrane, enhancing membrane endocytosis [146]. In addition, some environmental conditions, such as the gradient of ionic concentrations between the cytosol and extracellular medium, the additional magnetic [147, 148] and electric field [123] also show significant influence on the NP-membrane interaction. For example, Tian et al. [149] and Ding et al. [150] indicated that the NP-membrane interaction is affected by pH value for pH-sensitive dendrimers or some NPs modified by pH-sensitive polymers, which are in agreement with experimental observations.

5 Conclusions Understanding the interaction mechanism between the nanoparticles (NPs) and the membrane can prevent the undesirable side effects while using NPs as transport machine for drug delivery. The factors, which influence the interaction between the NPs and the membrane, can be divided into


different categories; the (physical and chemical) properties of NPs and those for membrane. Although extensive experimental studies have been reported in previous literature in order to understand the NP-membrane interaction, much less is known about the molecular details of the interaction mechanism and the kinetic evolution of these interaction processes. In this aspect, computer simulation techniques provide a complimentary tool to study the NP-membrane interaction. Therefore, coarse grained molecular dynamics (CGMD) and dissipative particle dynamics (DPD) simulations have been extensively used for investigating the interaction mechanism and corresponding interaction pathway. these studies undoubtly throw light on the mechanisms behind interaction of NPs with the plasma membrane, which not only helps us understand the involved bioprocesses, but also provides a design guideline for new NPs. Although numerous computer simulation studies on the NP-membrane interaction appear, some caution is needed in comparing the experimental and simulation results. Currently, the direct comparison of simulated results to their in vivo experimental counterparts is at most qualitative. This is partly because of the complex cellular environment that is insufficiently described in computer simulations. For example, in biological fluids some NPs may be immediately covered with proteins and other biomolecules, and therefore the interaction with the membrane would be mainly governed by the interaction with these proteins [151]. The formation of the layer of proteins changes the NP properties by simply lowering the surface free energy, and significantly affects the NP-membrane interaction. To understand in vivo NPmembrane interaction, we have to investigate the cell binding of proteins, which is rarely explored by computer simulations. This work was supported by the State Key Laboratory of Chemical Engineering (SKL-CHE-12B02) and the National Natural Science Foundation of China (21276007). The authors thank CHEMCLOUDCOMPUTING of BUCT, and the Super-computing Center, CNIC, CAS for providing computer time. 1 Allen TM, Cullis PR. Drug delivery systems: entering the mainstream. Science, 2004, 303: 1818–1822 2 Connor EE, Mwamuka J, Gole A, Murphy CJ, Wyatt MD. Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. Small, 2005, 1: 325–327 3 Gao H, Shi W, Freund LB. Mechanics of receptor-mediated endocytosis. Proc Natl Acad Sci USA, 2005, 102: 9469–9474 4 Ghosh P, Han G, De M, Kim CK, Rotello VM. Gold nanoparticles in delivery applications. Adv Drug Delivery Rev, 2008, 60: 1307–1315 5 Meyers MA, Mishra A, Benson DJ. Mechanical properties of nanocrystalline materials. Prog Mater Sci, 2006, 51: 427–556 6 Shubayev VI, Pisanic II TR, Jin S. Magnetic nanoparticles for theragnostics. Adv Drug Delivery Rev, 2009, 61: 467–477 7 Geng Y, Dalhaimer P, Cai S, Tsai R, Tewari M, Minko T, Discher DE. Shape effects of filaments versus spherical particles in flow and drug delivery. Nat Nanotechnol, 2007, 2: 249–255 8 Paciotti GF, Myer L, Weinreich D, Goia D, Pavel N, McLaughlin RE, Tamarkin L. Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Delivery, 2004, 11: 169–183

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