Surface Reconfiguration of Binary Lipid Vesicles via Electrostatically

Subscriber access provided by - Access paid by the | UCSB Libraries

Article

Surface Reconfiguration of Binary Lipid Vesicles Via Electrostatically-induced Nanoparticle Adsorption Fikret Aydin, and Meenakshi Dutt J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b02334 • Publication Date (Web): 24 Jun 2016 Downloaded from http://pubs.acs.org on June 28, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Physical Chemistry B is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Surface Reconfiguration of Binary Lipid Vesicles Via Electrostatically-induced Nanoparticle Adsorption

Fikret Aydin and Meenakshi Dutt** Department of Chemical and Biochemical Engineering Rutgers The State University of New Jersey, Piscataway, NJ 08854

** corresponding author: [email protected], +1 848-445-5612

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 39

ABSTRACT We demonstrate the adsorption of nanoparticles (NPs) with charged patches onto a binary vesicle encompassing polar neutral and polar zwitterionic lipids, via an implicit solvent coarsegrained model and molecular dynamics simulations. Our investigations on the interactions between NPs and a binary vesicle demonstrate that the adsorption of charged NPs onto a binary vesicle surface can induce structural reorganization of the lipid bilayer. The approach of the NP to the vesicle surface is accompanied by the spatial reorganization of the zwitterionic lipids and the degree of the reorganization is found to depend on the NP patch size. The interfacial adsorption of the NP is observed to promote a group of zwitterionic lipids to cluster at the adsorption site. The spatial reorganization of the zwitterionic lipids is activated by favorable electrostatic interactions with the NPs, and not between the lipids. The favorable electrostatic interaction between oppositely charged lipid head group moieties increases and assists the clustering process as the NP approaches the vesicle surface. In addition, the availability of the zwitterionic lipids in the vesicle affects the adsorption dynamics of multiple NPs. Our results can be used for the design of reconfigurable biomaterials for applications in drug delivery, sensing and imaging.


2

Page 3 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


INTRODUCTION Peripheral membrane proteins such as cytochrome c, protein kinase c (PKC), phospholipase A2 (LPLA2), phospholipase C (PLC)1-3 have been attributed to promote intra- and extracellular communication with electrostatic forces mediating1,4 the interactions with lipid domains in the cell membrane.5,6 Errors in cellular processing of information is responsible for a wide range of diseases including cancer, autoimmunity and diabetes.7 The interplay between the activities of membrane proteins and phase formation in the membrane has an important role in regulating signal transduction in the cell. For example, G protein-coupled receptors (GPCRs) are shown to induce the arrangement of lipid molecules into the hexagonal phase8 which in turn facilitate the conformational change of GPCR and its activation as well as the co-localization of signaling components such as G protein.9 Finally, activated GPCRs mediate signaling operation by activating many G proteins. Therefore, the phase formation in the membrane is critical for the interfacial binding events on the cell surface, and responsible for promoting intra- and extracellular communication. In this paper, we examine the impact of the electrostaticallyinduced binding and adsorption of nanoparticles on the surface reconstruction or local phase transition of a lipid vesicle.

Synthetic nanoparticles can be considered as simplified representation of proteins interacting with the membrane. The binding of charged NPs on a membrane has been reported to induce local phase changes and reorganization of specific molecules into distinct domains.10 In addition, cell membrane- nanoparticle (NP) interactions can result in their internalization by engulfment, or adsorption. Neutral and negatively charged NPs have been observed to adsorb onto negatively charged cancer cell membranes without being internalized in contrast to


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 39

positively charged NPs, which have a higher chance of being internalized by the cells.11 Small differences in the hydrophobicity, charge, shape and size of the NPs has been observed to significantly impact their adsorption onto or uptake by cells.12,13 The size and shape of NPs affect the physical state of the membrane such freezing, wrapping and pore formation.14 Interactions of small (1 to 20 nm), medium (20 to 50 nm) and large (50 to 200 nm) NPs with the membrane respectively favor pore formation, freezing and wrapping behaviors of the bilayer.14 The NPs with large planar surfaces as opposed to irregular surface or small particle radii can maximize their interactions with the membranes.14 A computational work based on coarse-grained molecular dynamics demonstrates the penetration of NPs into the lipid bilayer to be favored by the presence of planar surfaces.15 They found the penetration of pyramidal and faceted riceshaped NPs into the bilayer to be easier than conical and rod-like NPs, respectively. In addition, the rate of cellular uptake of spherical particles is shown to be five times more than rod-shaped particles by experimental investigation on the interactions of gold nanoparticles with Hela cells.16 This difference is considered to result from the longer time required for rod-shaped particles to be wrapped by the membrane. Another computational study based on dissipative particle dynamics (DPD) found similar results by demonstrating that the rate of endocytosis is faster for spherical particles than rod-shaped particles.17 The shape and size of the proteins are found to affect domain formation and membrane shape.18,19 The expansive parameter space dictating cell membrane-NP interactions requires the use of computational methods to understand the impact of NP particle characteristics on the dynamics and spatial organization of cell membrane components. We are interested in understanding the role of electrostaticallyinduced binding of patchy NPs onto a binary vesicle on the dynamics and spatial organization of the lipids, prior to and following interfacial adsorption. The patchy NP is a simplified


4

Page 5 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


representation of amphiphatic peripheral membrane proteins1 which have charged moieties that can bind to specific lipid domains on cell membranes. A fundamental understanding of the mechanisms underlying the electrostatically-mediated binding and interfacial adsorption of the peripheral membrane proteins or the patchy NPs onto the lipid domains can accelerate the development of new therapeutic strategies. Furthermore, this knowledge can guide the design of material platforms for nanolithography on soft surfaces, cellular sensors and adaptive cellular networks where cells are connected via inorganic nanowires or nanoparticles for applications in medicine, energy or sensing. Numerical studies of the interactions between charged NPs and bilayers must be able to resolve the relevant spatiotemporal scales to capture the mechanism of surface reconstruction in multi-component vesicles. All-atom simulations are limited to small spatio-temporal scales as they are computationally expensive.20-22 These tools are not suitable for addressing phenomena occurring on the mesoscale, such as membrane fusion and rupture, or reorganization of lipid molecules promoted by the adsorption of NPs onto multicomponent membranes.23 Dynamics spanning large length and time scales can be resolved via coarse-graining24-29, implicit solvent approaches20,23,30-32 or mean field theoretical techniques.33-37 The interactions between nanoparticles interacting with lipid bilayers have been investigated by using various theoretical and computational methods including the MD simulation method.38-44 Haugen and May investigated the effect of zwitterionic lipids on the electrostatic adsorption of macro-ions onto a mixed lipid membrane by using a modified version of the Poisson-Boltzmann theory by considering the dipolar nature of the zwitterionic lipids.45 They demonstrated the zwitterionic lipids to have different effects on the binding strength of macro-ions depending on the ionic properties of the membrane and macro-ions. Reynwar et al. investigated the effects of curvature-


5


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 39

inducing model proteins on membrane remodeling by using coarse-grained simulations.46 Their results showed that membrane curvature alone is capable of generating attractive interactions between proteins adsorbed on the membrane, and these attractive interactions result in subsequent protein cluster formation and vesiculation. Harries et al. developed a theoretical model to study interactions between a mixed membrane composed of neutral and charged lipids, and an oppositely charged protein.47 Their findings demonstrate that a minimal charge is required for a protein to transit from the adsorbed to wrapped state, and this transition point depends on the bending rigidity and spontaneous curvature of the lipid bilayer. Faraudo and Martin-Molina studied the binding of a DNA molecule onto a phosphatidylserine (PS) membrane that has a net negative charge by using molecular dynamics (MD) simulations.48 Their simulations confirmed a possible mechanism for a DNA molecule to adsorb onto a negatively charged membrane. They demonstrated adsorption of divalent cations to induce a structural change in the membrane that allows direct interaction of DNA with PS. Spangler et al. investigated the interactions of small spherical NPs with tensionless membranes by using implicit solvent MD method, and they found that NPs are unbound and partially wrapped respectively at low and intermediate values of adhesion strength, and completely wrapped or endocytosed at the large values of adhesion strength.49 We have adopted an implicit solvent coarse-grained model along with the MD technique to investigate the effects of NP adsorption on the surface reconstruction of a multicomponent vesicle. Implicit solvent models have been shown to reproduce many important features of the lipid bilayers. The physical properties of the lipid membranes obtained from implicit solvent models are shown to be same as those of an explicit solvent model with similar lipid resolution.50,51 In addition, elastic properties of the lipid bilayers such as area compressibility and


6

Page 7 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


bending modulii are found to be comparable to those in biological systems23,52 Furthermore, the phase transition properties of liposomes such as freezing behavior53 or domain formation54 as well as phase coexistence in the lipid membrane with an experimentally matched line tension55 are well captured by implicit solvent models. The interactions between nanoparticles and membrane are also investigated by a number of studies using implicit solvent models. Important phenomena involving membrane – nanoparticle interactions are captured with these models; for example, the equilibrium phase behavior of NPs being engulfed by lipid bilayers although the kinetics are not well described due to the lack of hydrodynamic interactions,49 the thermodynamics of the insertion of charged nanoparticles into lipid bilayers13 and the biophysical mechanism of NP wrapping by lipid membranes.44In this paper, we use a reduced model23,56 for two-tail lipid molecules and charged patchy NPs to investigate the effect of NP adsorption on the surface reconstruction of a binary vesicle composed of polar neutral and polar zwitterionic lipid molecules. This model is based on the use of broad attractive potentials between the hydrocarbon tail beads which enables the formation of a fluid lipid bilayer in the absence of solvent, and the use of continuum electrostatics which models the interactions between charged groups. Our results could potentially be used to design novel responsive biocompatible material platforms for applications in medicine, sensing or energy.57-59

METHODS The particle dynamics is resolved by using the classical molecular dynamics (MD) simulation technique.60-62 The equation of motion for each bead i is given by Fi = mi ai where Fi


7


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 39

is the force acting on bead i, mi is the mass and ai is the acceleration of the bead i. The force can be expressed as the gradient of the potential energy U by the relations Fi = −∇iU with

U = U pair + U elec + U bond + U angle , where Upair, Uelec, Ubond and Uangle are the potential energies from all its pair, screened electrostatics, bond and angle interactions, respectively. The dynamics of each bead i can be determined by the following equations − ∇ iU = mi a i = mi

∂ 2ri ∂v = mi i and 2 ∂t ∂t

vi = r&i , where ri and vi are the position and velocity vectors of bead i. The equations of motion are integrated using the Velocity Verlet method62 which has greater stability, time reversibility and preserves the symplectic form in the phase space compared to the Euler method.62 The MD simulations sample the canonical ensemble with a Langevin thermostat and are run using the open source parallelized MD program entitled LAMMPS.63 In this paper, we use a coarse-grained model of a two-tail lipid molecule to investigate the interaction between a binary vesicle encompassing polar neutral and polar zwitterionic lipids and NPs functionalized with negatively charged moieties. We study the role of the interactions between the charged groups on the reconstruction of the bilayer surface, the processes underlying the NP adsorption and the post-adsorption dynamics of the molecular components in the bilayer. We introduce an implicit solvent model56 with screened electrostatic interactions based upon an earlier model introduced by Cooke and Deserno.23 Our system consists of a stable, preassembled multicomponent vesicle composed of zwitterionic and neutral lipid molecules, and NPs with charged groups. The head groups of zwitterionic lipids have dipolar nature, as opposed to the lipids with a net charge. The interactions of negatively or positively charged nanoparticles with zwitterionic lipids and lipids with a net charge will differ since both repulsive and attractive


8

Page 9 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


interactions are playing a role in the case of zwitterionic lipids while the interactions will be either purely repulsive or attractive when there is a net charge on the head groups of lipid molecules. The influence of the presence of zwitterionic lipids in the membrane on the adsorption of macro-ions has been demonstrated in a previous theoretical study.45 A lipid molecule is represented by a bead-spring model with one head group encompassing three hydrophilic beads and two hydrocarbon tail groups composed of three hydrophobic beads each, as shown in the Fig. 1 (a). Positive and negative charges are added to the two hydrophilic beads in the head group of the zwitterionic lipid molecules, as shown in Fig. 1 (b). Experimental examples of zwitterionic and neutral lipid molecules include dipalmitoylphosphatidylcholine (DPPC) and 1,2-dipalmitoyl-sn-glycerol, or ceramide 3, respectively. The mixtures of DPPC and Ceramide 3 lipid molecules were used in the experiments to investigate the effect of Ceramide 3 content on the liposome formation, particle size, dispersibility, microviscosity and phase transition temperature.64

Figure 1. Images of the (a) polar neutral lipid molecule, (b) polar zwitterionic lipid molecule such as DPPC, and (c) spherical NP with a negatively charged patch. NP has a radius of 2.25rc.

The repulsive interactions due to the excluded volume effects between the beads can be modeled

by

the

purely

repulsive

Weeks-Chandler-Andersen

(WCA)

potential65

U rep ( r, b) = 4 E [(b / r )12 − (b / r ) 6 ] + E (for r≤ rc), where E is the depth of the potential well, b is the bead diameter, r is the distance between two beads and rc is the cutoff distance beyond which the interactions are not computed. The cut-off distance is given by rc = 2(1/6) b. The repulsive


9


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 39

interactions between the head-head and head-tail beads are represented by the WCA potential.The van der Waals attraction between the beads can be suitably represented by a Lennard-Jones-style potential with its range extended via a tunable length wf: Uflat LJ(r) = −E (for r < rc + wf), U flat LJ ( r ) = 4 E[(b /( r − w f ))12 − (b /( r − w f )) 6 ] (for rc ≤ r ≤ wf + wcut) and

Uflat LJ(r) = 0 (for r > wf + wcut), where the potential is cutoff beyond wf + wcut.23,56 The underlying principle of this model is the use of a broad attractive potential Uflat LJ (r) between the tail beads to compensate for the absence of the solvent molecules. Here, wf is the length of the flat region at the minimum of the potential and wcut is the cut-off distance. In our simulations, we choose wf = 0.2σ and wc = 2.5σ. The value of rc depends on the type of the beads interacting with each other and it is controlled through the value of b. For the head-head and head-tail interactions, b is set to be 0.95σ and for tail-tail interactions, b is set to be σ. E is the unit of energy and σ is the unit of length. The interaction between the tail beads is obtained by combining the repulsive and attractive pair potentials to yield a combined pair potential Ucomb of the following form: U comb( r) = 4E[(b / r)12 − (b / r)6 ] (for r≤ rc), Ucomb(r) = −E (for rc < r < rc + wf), U comb ( r ) = 4 E[(b /( r − w f ))12 − (b /( r − w f )) 6 ] (for rc + wf ≤ r ≤ wf + wcut) and Ucomb(r) = 0 (for r > wf + wcut). The screened electrostatic interaction between the charged groups is modeled via the

e − kr Yukawa potential U ( r ) = A (for r < rcelec) where 1/k is the Debye screening length and rcelec r is the cutoff distance for the screened electrostatic interactions. The cut-off distance is chosen to be rcelec = 6σ. A is a constant which embodies the strength of the electrostatic potential and is given by A =

q1q2 where q1 and q2 are the charges, ε0 is the vacuum permittivity and ε is the 4πε 0ε


10

Page 11 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


dielectric constant of water. The strength of the screened electrostatic interactions will be determined by the concentration of the counterions. We choose 1/k = 1 nm which corresponds to the Debye length for a 0.1 M solution of a monovalent salt which is commonly used to approximate the cytoplasm.66 The DPPC phospholipid molecule has positively charged choline and negatively charged phosphate groups which bear charges +e and –e, respectively (e = 1.602x10-19 C). By using q1 = +e, q2 = -e, ε0 = 8.854x10-12 C2/Nm2 and ε = 80, we get A ~ ± kbT for the electrostatic interactions between charged groups of the DPPC phospholipid molecules. The counterions in our simulations are implicitly taken into account via the use of the Yukawa potential. In the Yukawa potential, Debye length determines the degree of screening caused by the counterions, and it is inversely proportional to the salt concentration. We chose the Debye length to correspond to physiological conditions in the simulations. Yukawa models can be applied to describe electrostatic interactions when there is a weak ion-ion coupling and charge correlation effects are negligible such that the Poisson-Boltzmann theory becomes valid.67 The screened Coulomb potentials such as Yukawa or Debye -Hückel have been used in a number of implicit solvent simulation studies to model electrostatic interactions of lipids68,69 and proteins.70,71 Jusufi et al. investigated the micellization properties of surfactants in the presence of explicit salt and compared these results to those obtained by using Yukawa type potentials.72 They demonstrated the Yukawa potential to reproduce the experimental results for the micellization of cationic dodecyltrimethylammonium chloride (DTAC) and anionic sodium dodecyl sulfate (SDS) surfactants. This study demonstrates applicability of the Yukawa potential in the absence of explicit ions even for phenomena that are highly dependent on the ionic conditions, such as the micellization of surfactants.


11


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 39

In the bead-spring representation of chain-like moieties, two consecutive beads along a chain are connected by an attractive finitely extensible nonlinear elastic spring (FENE)66 given 2 by U FENE (r ) = −0.5Kr∞ ln[1 − (r / r∞ ) 2 ] (for r < r∞) and UFENE(r) = ∞ (r ≥ r∞) where r is the

separation between the centers of mass of two bonded beads, r∞ is the maximum extension of the spring, or the divergence length and K is the spring constant. The stiffness and the divergence length are respectively given by K = 30E / σ2 and r∞ = 1.5σ. The bond potential parameters were selected to model a relatively stiff spring to avoid high frequency modes and chain crossing.23,73 The hydrophobic lipid tails are attributed stiffness through a harmonic angle potential U angle = Kθ (θ − θ 0 ) 2 where Kθ is the angle potential constant and is given by 8.1 E/ rad2. θ0 is the equilibrium angle between three consecutively bonded beads and is set to 3.14 rad (or, 180 degrees). The NPs, shown in Fig. 1 (c), are hollow spheres composed of 312 hydrophilic beads with a patch covering 20% of the surface and radii of 2.25σ. The radius of a NP is defined to be the distance spanning the center of the NP to the outer surface of the beads. The patch is negatively charged (or, anionic) so it has favorable interactions with the positively charged moiety of the zwitterionic lipid head group. The remaining part of the NP is modeled as electrostatically neutral. Experimental counterparts of the NPs can be proteins, drug molecules or synthetic particles with moieties grafted on to their surface.74 We model the complex topography and asymmetric charge distribution of NPs via patchy spherical counterparts.75 Negatively charged NPs can be obtained by modifying the surface of white polystyrene latex with carboxyl groups (~0.91e-/nm2).10 The surface area of the NP patch is found to be 4.4 nm2, which corresponds to qpatch ~ 4e- by using the charge density of 0.91 e-/nm2.


For the attractive

12

Page 13 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


interactions between the negatively charged patch and the positively charged lipid head bead, the Yukawa potential parameter A is found to be -4kBT. Similarly, for the repulsive interactions between the negatively charged patch and the negatively charged lipid head bead, A is given by +4kBT. In addition, the A parameter for patch – patch interactions is set to +16kBT by using the previously defined relation A =

q1q2 . All the remaining interactions between the NP and the 4πε 0ε

lipid molecules are described by the WCA potential with E = 1, rc = 2(1/6) b and b = σ. The simulations were run in the canonical ensemble using the Langevin thermostat with three dimensional periodic boundary conditions. The simulation box dimensions were set to 60σ x 60σ x 60σ. The total number of beads in the system was 36000 which corresponds to a lipid density of 0.019 lipids per σ3. The simulation time step was set to δt = 0.01τ.

RESULTS AND DISCUSSION We begin with a preassembled binary vesicle encompassing 1:2 mixture of polar zwitterionic and polar neutral lipids, which is placed in a simulation box of dimensions 60 σ x 60 σ x 60 σ. The total number of lipid beads in the simulation box is 36,000. The simulation box has periodic boundaries along the three coordinate axes, with a total of 4000 zwitterionic and neutral lipid molecules. A stable mixed vesicle is obtained in a simulation spanning a time interval of 100,000τ. The radius of the vesicle is measured as 22 σ. The size of the vesicles has no effect on the observed interactions between nanoparticles and lipid molecules, as demonstrated by a previous experimental work,10 thus a single vesicle size is used in this work. We introduce a NP with a medium patch (corresponding to 20% of the NP surface area) at an arbitrary position in


13


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 39

the simulation box such that it is outside the interaction range from the vesicle, as shown in Fig. 2 (a). Our results show the NP to diffuse randomly in the simulation box until the NP patch and the lipid head groups are within interaction range from each other. The change in the orientation of the NP patch before its adsorption on to the vesicle surface can be observed in Fig. 2 (b) as well as in the Movie S1 of the Supporting Information. Attractive interactions between the negatively charged NP patch and positively charged choline group of the DPPC lipid molecules enable the adsorption of the NP onto the vesicle surface, as demonstrated in Fig. 2 (c) and in the Movie S1. The final equilibrium configuration of the adsorbed NP on the vesicle surface at time t = 120,000 τ is provided in Fig. 2 (d). The diffusion and adsorption processes of the NP are characterized by the time evolution in the number of interactions between the NP patch and the head groups of zwitterionic lipids, as shown in Fig. 2 (e). A pair of beads is considered to be interacting if their center-to-center distance is less than the cut-off distance (rc = 1.07) based on the WCA potential. This cut-off distance was chosen to discern nearest-neighbor interactions between oppositely charged moieties. The NP diffuses for a time interval spanning 70,000 τ, during which there are no interactions between the NP patch and the lipid head groups. The interaction count abruptly increases at 70,000 τ when the NP patch is within interaction range from the zwitterionic lipid head groups. As the NP patch approaches and adsorbs onto the vesicle surface, the interaction count increases and reaches a steady state value around 80,000 τ. We determine the binding energy of the adsorbed NP at the steady state by using the following formula:76 Ebinding = EYukawa (NP-lipids) + Evdw (NP-lipids) – Evdw (NP-solvent), where EYukawa (NP-lipids) and Evdw (NP-lipids) are respectively electrostatic and van der Waals interaction energies between the adsorbed nanoparticle and the head groups of zwitterionic lipids within the interaction region of the NP patch. Evdw (NP-solvent) is the van der Waals interaction energy


14

Page 15 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 2. Images of the capture of a NP with a negatively charged patch by positively charged choline groups of lipid molecules in a binary component vesicle composed of zwitterionic lipids (33%) and neutral lipid molecules (67%) at time (a) t = 0, (b) t = 65,000 τ, (c) t = 70,000 τ and (d) t = 120,000 τ. (e) A plot of the number of interactions between the NP patch and the zwitterionic lipid head groups, and between oppositely charged head beads of zwitterionic lipids interacting with the NP patch as a function of time, during the capture process.


15


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 39

between the NP and the solvent, which is zero in the implicit solvent simulations. The binding energy per the area of contact is calculated to be 1.95 kbT/σ2 (σ is the length scale of the system), where the area of contact is defined as the region within the interaction range of the NP patch. This value is found to be close but higher than the previously reported binding energy (0.49 kbT/nm2) of a charged NP onto the DPPC lipid molecules76 (considering σ is less than 2 nm). The reason for this difference could be the lack of the interactions between the NP and solvent as well as the difference in the charge density of the NPs. The adsorption of the NP is accompanied by the clustering of zwitterionic lipids whose positively charged head groups have favorable enthalpic interactions with the negatively charged patch. A cluster is defined as a group of zwitterionic lipids whose headgroup beads are within interaction range from each other. The cluster in the vesicle bilayer onto which the NP remains adsorbed encompasses about 9 zwitterionic lipids, which is the average number of zwitterionic lipids interacting with the NP charged patch. We expect this number to increase with a larger area of the NP charged patch as there will be more binding sites for zwitterionic lipids to adsorb. This expectation is validated by repeating the same analysis for NPs with small and large patches (corresponding to 10% and 30% of the NP surface area), which are found to be interacting with 5 and 14 zwitterionic lipids, respectively. In addition, the difference in the adsorption processes of the NPs with varying patch sizes is demonstrated in Fig. 3 that shows the time evolution in the number of interactions between the NP patch and the head groups of polar zwitterionic lipids.


16

Page 17 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3. A plot of the number of interactions between the NP patch (small, medium and large) and the zwitterionic lipid head groups as a function of time for a single NP adsorption onto the vesicle surface.

To understand the mechanism underlying the clustering of the zwitterionic lipids, we examined the time evolution of interactions between the oppositely charged moieties in the head groups of the lipids in the cluster (see Fig. 2(e)). We observe some of zwitterionic lipids to interact with each other prior to the adsorption of the NP due to the favorable enthalpic interactions between their oppositely charged moieties. The interactions between the patch and the lipid head groups enhances the favorable electrostatic interactions between the zwitterionic lipid head groups until the NP adsorbs onto the cluster of lipids. We surmise that the clustering of zwitterionic lipid molecules is promoted by the interactions with the NP, and is activated by the initial interactions between the NP patch and the vesicle bilayer. Following the adsorption of the NP, we observe occasional interactions between the neutral moieties in the head groups of the zwitterionic lipid molecules and the negatively charged patch (see Fig. 2 (e)). We do not observe any interaction between the NP patch and neutral lipids.


17


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 39

The approach of the NP patch towards the vesicle surface was observed to influence the motion of the zwitterionic lipids in the bilayer. In order to understand the phenomena of electrostatically-induced surface reconstruction, we examine the clustering of zwitterionic lipids which are within interaction range from the NP by varying the distance between the NP patch and the vesicle surface from 2 σ to 6 σ with increments of 0.5 σ, and determine the effect of the patch size on the clustering. The centers of mass of the NP and the vesicle are kept fixed at their initial positions and with respect to each other, as shown in Fig. 4.

Figure 4. A schematic of the system setup for the clustering analysis where the separation distance between the NP patch and the vesicle surface is varied from 2 σ to 6 σ with increments of 0.5 σ while keeping the centers of mass of the NP and vesicle fixed at their initial positions and with respect to each other.

The simulations are run for a time interval of 100,000 τ, and the results are obtained by averaging the measurements during the final 20,000 τ of the interval. For consistency between the clustering results at different distances between the NP patch and the vesicle surface, we identify the zwitterionic lipid molecules that are within interaction range from the NP patch for


18

Page 19 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the smallest separation distance (2 σ). We identify 17, 19 and 20 lipid molecules, respectively for the small, medium and large patches that are used for the clustering measurements at different separation distances. The results for the number of clusters and average cluster size are summarized in Table 1.

Table 1. Effect of NP patch size and its distance to the vesicle surface on the lipid clustering

Our results demonstrate that cluster formation is activated when the separation distance is less than or equal to 3.0 σ as supported by the decrease in the number of clusters, or an increase in the average cluster size. The large NP patch is found to have a greater influence on the number of clusters and average cluster size of polar zwitterionic lipids. The Movies S2 and S3 demonstrate the presence and absence of cluster formation for separation distances of 2.5 σ and 3.5 σ, respectively for the medium NP patch. We also calculate the average velocity field of the


19


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 39

selected zwitterionic lipid molecules at various separation distances between the medium NP patch and vesicle surface, as shown in Fig. S1. The results for the average velocity field are obtained by averaging the measurements over the first 20,000 τ of the time interval spanning 100,000 τ. The results show the magnitude of the difference in the maximum velocities in opposite directions to increase as the separation distance falls below 3.0 σ on account of the stronger electrostatic attraction between oppositely charged moieties. We examine the simultaneous adsorption of multiple NPs by introducing 24 NPs with medium patches at randomly selected positions in the simulation box such that their centers of mass are 6σ away from the vesicle surface, and thereby at the limit of the interaction range from the lipids (see Fig. 5 (a)). The choice of the initial distance was determined by the need to resolve the adsorption dynamics of multiple NPs within a reasonable duration of time. The adsorption of the NPs is promoted by the favorable electrostatic interactions between the negatively charged NP patch and the positively charged moiety in the zwitterionic lipid head group, as shown in Fig. 5 (b). We observe the vesicle to maintain its structural integrity during the multiple adsorption processes. These observations are consistent with a previous study which demonstrated the absorption of anionic and cationic NPs onto the phosphatidylcholine group of lipids composed of negatively charged phosphate and positively charged choline. In addition, the liposomes were reported to have maintained their integrity in the presence of the adsorbed NPs.77 We ran the simulations until all the NPs interfacially adsorbed onto the vesicle surface. The characterization for each system uses particle trajectories from four simulations which have identical initial conditions but different random seeds.


20

Page 21 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 5. (a) Initial configuration of a binary vesicle and 24 NPs randomly placed away from the vesicle surface. (b) The 24 NPs adsorbed onto the lipid head groups at time t = 120,000τ.

We examine the time evolution in the interaction count between the negatively charged patch of the 24 NPs with medium patches and the positively charged moiety of the lipid head groups, as shown in Fig. 6. We observe the adsorption of the NPs onto the vesicle is accompanied by a steep increase in the number of interactions between the patch and the head groups, before reaching a steady state value. The clustering of zwitterionic lipid molecules is

Figure 6. Plot of the number of interactions between the negatively charged NP patch and positively charged lipid head groups, and between oppositely charged head beads of zwitterionic lipids interacting with NP patch as a function of time, for 24 NPs in the system. The simulations have been run for a total time of 120,000τ. The interaction count has been averaged over four simulation runs using different random seeds.


21


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 39

found to correlate with increasing number of interactions between the NP patch and charged lipid head groups. The number of lipid molecules interacting with each NP patch is found to be in the range of 6 - 12. We find that prior adsorbed NPs do not affect the number of lipid head groups interacting with the subsequently adsorbing NPs. Hence, the available population of lipids does not influence the adsorption dynamics of multiple NPs. In order to understand the effect of available zwitterionic lipid molecules and the size of NP patch on the adsorption dynamics of multiple NPs, we vary the concentration of zwitterionic lipids in the vesicle and introduce 24 NPs with small, medium and large patches. We decrease the concentration of zwitterionic lipids from 33% to 8.3% based on the number of lipids interacting (14) with the large NP patch from the study of a single NP adsorption. Fig. 7 (a) shows the time evolution in the number of interactions between the NP patch and the head groups of zwitterionic lipids for the cases of low (8.3%) and high (33%) concentration of zwitterionic lipids and NPs with small, medium and large patches. Similar to the results of single NP adsorption, the number of interactions decreases as the patch size gets smaller both for low and high concentration of zwitterionic lipids. Our results demonstrate that the available population of zwitterionic lipids affects the adsorption dynamics of multiple NPs as the number of interactions significantly decrease with lower concentration of zwitterionic lipids. One of the reasons for this decrease is inability of some of the NPs to adsorb onto the vesicle. A visual inspection (as shown in Fig. 7 (b)) demonstrates the availability of zwitterionic lipids for remaining NPs to adsorb but these lipid molecules are spatially scattered on the vesicle surface (as opposed to several zwitterionic lipids localized in a specific region), which can affect the adsorption dynamics of NPs. Another reason for the decreased number of interactions is the presence of fewer zwitterionic lipids interacting with the NPs at low concentration in comparison to those at high concentration.


22

Page 23 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 7. (a) Plot of the number of interactions between the negatively charged NP patch and positively charged lipid head groups as a function of time, for 24 NPs with small, medium and large patch and mixed vesicle with low (8.3%) and high (33.3%) concentrations of zwitterionic lipids. (b) Final configuration of a mixed vesicle with a low concentration of zwitterionic lipids and 24 NPs with medium patch.

For example, the average number of zwitterionic lipids interacting with the NPs with medium patch is 2 – 5 at low concentration of zwitterionic lipids and 6 – 12 at high concentration. We measure the residence time to understand the dynamics of the lipids interacting with the NPs


23


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 39

following their adsorption. For these investigations, NPs with medium patch and high concentration (33%) of zwitterionic lipids are used. We define the residence time as the number of times a lipid molecule is found to be interacting with a NP during a time interval spanning 80,000τ. For this measurement, we track the interactions between the lipid head groups and the NP patch at time intervals of 100τ. A lipid molecule can have a maximum residence time of 800 (80,000τ / 100τ) if it is interacting with a NP patch during the entire interval of the measurement. The residence time distribution for a system composed of 4000 lipid molecules and 24 NPs is obtained by binning the number of lipid molecules based upon their residence time, as shown in Fig. 8. Our results demonstrate that a large population of lipid molecules have long lived interactions with the NP patch, supported by the distribution favoring higher residence times.

Figure 8. Residence time measurements of 24 NPs after their adsorption on to the lipid head groups of binary vesicle composed of zwitterionic and neutral lipid molecules.

This behavior arises from the formation of isolated clusters of zwitterionic lipid molecules onto which the NP patch is adsorbed. We demonstrate the formation of the clusters upon the


24

Page 25 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


adsorption of NPs on to the vesicle surface, as shown in Figs. 9 (a) and (b). The reconfiguration of the vesicle surface by the formation of small clusters can be measured by the number of interactions between the head groups of the zwitterionic lipid molecules, as shown in Fig. 9 (c). We surmise that the strong electrostatic interactions between lipid head groups and NP patches prevent the lipid molecules from diffusing away from the interaction range of the NP patch.

Figure 9. (a) Initial configuration of zwitterionic lipid molecules within the interaction range from the NPs, before their adsorption. (b) Formation of small domains composed of zwitterionic lipid molecules upon adsorption of NPs on to the vesicle surface. (c) Plot of the number of interactions between lipid head groups as a function of time, during the adsorption of the NPs on to the vesicle surface.


25


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 39

A previous experimental study10 demonstrated the formation of local gel phases in a vesicle composed of PC lipids due to interactions with negatively charged NPs, and suggested that these local phases arose from the reorientation of the lipid head groups resulting in closer packing of the lipid molecules. Another study also demonstrated the change in the orientation of lipid head groups due to their interactions with charged NPs by using self-consistent field calculations.78 We also examined the physical properties of the mixed vesicle by measuring the area per lipid and the bilayer thickness, and investigated the effects of NP adsorption on these properties. In order to characterize the physical properties of the mixed vesicle, we obtain the physical length scale of the system by measuring the area per lipid from the simulations and comparing the results to the experimental values. Since there are no experimental measurements for the area per lipid for the system investigated in this paper, an approximate area per lipid is calculated by considering Ceramide (C16) and DPPC lipids as examples of polar neutral and polar zwitterionic lipids, respectively. The area per lipid of fluid ceramides with hydrophobic tails encompassing twelve or more acyl groups has been found to be approximately 0.46 nm2 by using all-atom simulations.79 On the other hand, fluid DPPC bilayer has an area per lipid80 of approximately 0.64 nm2. If the contribution of each lipid molecule to the overall area per lipid is assumed to be proportional to their fraction in the bilayer, the average area per lipid for the mixed vesicle (Cer16:DPPC=2:1) is calculated to be 0.52 nm2 (0.64 nm2 x (1/3) + 0.46 nm2 x (2/3)). The average area per lipid of the simulated mixed vesicle is computed by dividing the bilayer into multiple rectangular patches so that each patch can be treated as a bilayer membrane. The average area per lipid is computed by summing the areas of all the patches, and dividing by the total number of lipid molecules in the vesicle bilayer. Using the value for the area per lipid (2.1±0.1 σ2) computed for a stable two-component vesicle, the length scale for the model is σ =


26

Page 27 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.49 nm. Similarly, the bilayer thickness is computed by measuring the distance between the lipid head groups in the opposing monolayers in a given patch. These measurements were computed for each patch and averaged over all the patches as well as the various particle configurations. For the vesicle composed of polar neutral and polar zwitterionic lipids (2:1), the average bilayer distance is found to be 6.8±0.2 σ which corresponds to 3.3±0.1 nm in physical units. The bilayer thickness (head to head) of pure Cer16 bilayer is measured to be approximately 4 nm using all-atom simulations,79 whereas the DPPC bilayer has a bilayer thickness computed using theory and atomic force microscopy of 3.3 nm and 3.6 nm, respectively.81 Our results are in good agreement with these findings given that the lipid models are highly coarse-grained, and the Cer16 and DPPC molecules are approximate representations of polar neutral and polar zwitterionic lipids, respectively. In addition, there is variability in the measurements from various methods employed to determine the bilayer thickness. We investigated the effect of NP adsorption on the area per lipid and bilayer thickness of the vesicle by measuring these bilayer properties when the NPs are adsorbed on the surface of the vesicle. In order to be able to distinguish the effects caused by the adsorption of the NPs, only the area of the vesicle bilayer within the interaction range of the NP patch is investigated. The area per lipid is found to decrease with the adsorption of the NPs (as visually demonstrated in Fig. 9 (a) and (b)), and the degree of reduction in the area per lipid is found to increase with increasing patch size, as shown in Table 2. In addition, the bilayer thickness is found to increase slightly with the adsorption of NPs, and this increase is found to be similar for all three patch sizes. The reason for this increase could be the reduction in the conformational entropy of the lipids as they pack closely together due to the attraction to the oppositely charged NP patch.


27


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 39

Table 2. Effect of NP adsorption on the area per lipid and bilayer thickness of the vesicle

CONCLUSIONS We studied the electrostatically-induced interfacial adsorption of charged patchy NPs onto a mixed vesicle composed of polar neutral and polar zwitterionic lipids, via the MD simulation technique. We introduced screened electrostatic interactions in an earlier coarsegrained implicit solvent model23,57 via the Yukawa potential. This model enabled us to simulate large systems with long-range electrostatic interactions. The approach of a NP to a vesicle bilayer surface was observed to influence the spatial dynamics of the zwitterionic lipids in the bilayer. We identified a critical separation distance between the NP patch and the vesicle surface for the inducement of cluster formation. We also determined the effect of varying the size of the NP patch on cluster formation and found increasing degree of clustering with larger patches. The electrostatic interactions between the NP patch and the choline groups of the zwitterionic lipids were observed to promote the clustering of the lipids accompanied by the interfacial adsorption of the NP on to the cluster. Our investigations on the interfacial adsorption of multiple NPs demonstrated the NPs to be localized on the surface of the vesicle, characterized by the longlived interactions between the NP patch and lipid head groups. We demonstrated the availability of the zwitterionic lipids in the vesicle to affect the adsorption dynamics of multiple NPs. We observed the vesicles to maintain their integrity in the presence of the adsorbed NPs, which is found to be consistent with a previous experimental study.77 Our investigations demonstrate the


28

Page 29 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


adsorption of charged NPs on to the vesicle surface to induce spatial reorganization in the lipid bilayer, resulting in the formation of small clusters of a particular lipid specie. These results are consistent with an earlier experimental study which demonstrates the reconstruction of the vesicle surface due to its interactions with negatively charged NPs. Finally, we examined physical properties of the mixed vesicles such as the area per lipid and the bilayer thickness, and demonstrated the adsorbed NPs to influence these properties. These studies can be used to design nanoscale probes to imprint dynamic interfaces for directed assembly of nanocolloids for applications in sensing, medicine and electronics.

Supporting Information. One movie showing the change in the orientation of the nanoparticle patch before its adsorption on to the vesicle surface; two movies showing the presence and absence of cluster formation for separation distances of 2.5 σ and 3.5 σ between the nanoparticle patch and the head groups of the polar zwitterionic lipids; one figure showing the average velocity field of zwitterionic lipid molecules within interaction range of the nanoparticle at various separation distances between the nanoparticle patch and vesicle surface. This material is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEDGEMENTS Portions of the research were conducted using high performance computational (HPC) resources at the Rutgers Discovery Informatics Institute (http://rdi2.rutgers.edu/) and HPC resources provided by Extreme Science and Engineering Discovery Environment (XSEDE) through allocations TG-DMR140125 and TG-DMR110109.


29


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 39

REFERENCES 1

Heimburg, T.; Angerstein, B.; Marsh, D. Binding of Peripheral Proteins to Mixed Lipid Membranes: Effect of Lipid Demixing upon Binding. J. Biol. Phys. 1999, 76, 2575–2586.

2

Marsha, D.; Horváthb, L.I.; Swamyc, M.J.; Mantripragadad, S.; Kleinschmidte, J.H. Interaction of Membrane-Spanning Proteins with Peripheral and Lipid-Anchored Membrane Proteins: Perspectives from Protein-Lipid Interactions. Mol Membr Biol. 2002, 19, 247–255.

3

Cho, W.; Stahelin, R. V. Membrane-Protein Interactions in Cell Signaling and Membrane Trafficking. Annu Rev Biophys Biomol Struct. 2005, 34, 119–151.

4

Sankaram, M. B.; Marsh, D. New Comprehensive Biochemistry 1993, 25, 127–162.

5

Lipowsky, R. Domains and Rafts in Membranes—Hidden Dimensions of Selforganization. J. Biol. Phys. 2002, 28, 195–210.

6

Simons, K.; Vaz, W. L. C. Model Systems, Lipid Rafts, and Cell Membranes. Annu. Rev. Biophys. Biomol. Struct. 2004, 3, 269.

7

Escribá, P.V.; González-Ros, J.M.; Goñi, F.M.; Kinnunen, P.K.; Vigh, L.; SánchezMagraner, L.; Fernández, A.M.; Busquets, X.; Horváth, I.; Barceló-Coblijn, G. Membranes: A Meeting Point for Lipids, Proteins and Therapies. J Cell Mol Med. 2008, 12, 829–875.

8

van der Wel, P.C.; Pott, T.; Morein, S.; Greathouse, D.V.; Koeppe II, R.E.; Killian, J.A. Tryptophan-Anchored Transmembrane Peptides Promote Formation of Nonlamellar Phases in Phosphatidylethanolamine Model Membranes in a Mismatch-Dependent Manner. Biochemistry 2000, 39, 3124–3133.

9

Vögler, O.; Barceló, J.M.; Ribas, C.; Escribá, P.V. Membrane Interactions of G Proteins and Other Related Proteins. Biochimica et Biophysica Acta (BBA) – Biomembranes 2008, 1778, 1640–1652.


30

Page 31 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


10 Wang, B.; Zhang, L.; Bae, S.C.; Granick, S. Nanoparticle-Induced Surface Reconstruction of Phospholipid Membranes. PNAS 2008, 105, 18171–18175. 11 Cho, E.C.; Xie, J.; Wurm, P.A.; Xia, Y. Understanding the Role of Surface Charges in Cellular Adsorption Versus Internalization by Selectively Removing Gold Nanoparticles on the Cell Surface with a I2/KI Etchant. Nano Lett. 2009, 9, 1080–1084. 12 Zhu, Z.-J.; Ghosh, P.S.; Miranda, O.R.; Vachet, R.W.; Rotello, V.M. Multiplexed Screening of Cellular Uptake of Gold Nanoparticles Using Laser Desorption/Ionization Mass Spectrometry. J. Am. Chem. Soc. 2008, 130, 14139–14143. 13 Van Lehna, R.C.; Alexander-Katz, A. Free Energy Change for Insertion of Charged, Monolayer-Protected Nanoparticles into Lipid Bilayers. Soft Matter 2014, 10, 648–658. 14 Rascol, E.; Devoisselle, J.-M.; Chopineau, J. The Relevance of Membrane Models to Understand Nanoparticles–Cell Membrane Interactions. Nanoscale 2016, 8, 4780–4798. 15 Nangia, S.; Sureshkumar, R. Effects of Nanoparticle Charge and Shape Anisotropy on Translocation through Cell Membranes. Langmuir 2012, 28, 17666–17671. 16 Chithrani, B.D.; Chan, W.C. Elucidating the Mechanism of Cellular Uptake and Removal of Protein-coated Gold Nanoparticles of Different Sizes and Shapes. Nano Lett. 2007, 7, 1542– 1550. 17 Li, Y.; Yue, T.; Yang, K.; Zhang, X. Molecular Modeling of the Relationship between Nanoparticle Shape Anisotropy and Endocytosis Kinetics. Biomaterials 2012, 33, 4965– 4973. 18 Frese, R.N.; Pàmies, J.C.; Olsen, J.D.; Bahatyrova, S.; van der Weij-de Wit, C.D.; Aartsma, T.J.; Otto, C.; Hunter, C.N.; Frenkel, D.; van Grondelle, R. Protein Shape and Crowding


31


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 39

Drive Domain Formation and Curvature in Biological Membranes. Biophys J. 2008, 94, 640– 647. 19 Zimmerberg, J.; Kozlov, M.M. How Proteins Produce Cellular Membrane Curvature. Nature Reviews Molecular Cell Biology 2006, 7, 9–19. 20 Farago, O. "Water-free" Computer Model for Fluid Bilayer Membranes. O. J. Chem. Phys.

2003, 119, 596−605. 21 Brannigan, G.; Brown, F.L.H. Solvent-free Simulations of Fluid Membrane Bilayers. J. Chem. Phys. 2004, 120, 1059. 22 Shillcock, J. C. Spontaneous Vesicle Self-Assembly: A Mesoscopic View of Membrane Dynamics. Langmuir 2012, 28, 541–547. 23 Cooke, I.R.; Deserno, M. Solvent-free Model for Self-assembling Fluid Bilayer Membranes: Stabilization of the Fluid Phase based on Broad Attractive Tail Potentials. J. Chem. Phys.

2005, 123, 224710. 24 Farago, O. Mode Excitation Monte Carlo Simulations of Mesoscopically Large Membranes. J. Chem. Phys. 2008, 128, 184105. 25 Dutt, M.; Kuksenok, O.; Nayhouse, M.J.; Little, S.R.; Balazs, A.C. Modeling the SelfAssembly of Lipids and Nanotubes in Solution: Forming Vesicles and Bicelles with Transmembrane Nanotube Channels. ACS Nano 2011, 5, 4769-4782. 26 Dutt, M.; Kuksenok, O.; Little, S.R.; Balazs, A.C. Forming Transmembrane Channels Using End-Functionalized Nanotubes. Nanoscale. 2011, 3, 240-250. 27 Shillcock, J. C.; Lipowsky, R. Equilibrium Structure and Lateral Stress Distribution of Amphiphilic Bilayers from Dissipative Particle Dynamics Simulations. J. Chem. Phys. 2002, 117, 5048–5061.


32

Page 33 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


28 Stevens, M.J. Coarse-grained Simulations of Lipid Bilayers. Chem. Phys. 2004, 121, 11942−11948. 29 Shih, A.Y.; Arkhipov, A.; Freddolino, P. L.; Schulten, K. A Coarse-Grained Protein-Lipid Model with Application to Lipoprotein Particles. J. Phys. Chem. 2006, 110, 3674–3684. 30 Wang, Z.; Frenkel, D. J. Modeling Flexible Amphiphilic Bilayers: A Solvent-Free OffLattice Monte Carlo Study. Chem. Phys. 2005, 122, 234711. 31 Brannigan, G.; Philips, P.F.; Brown, F.L.H. Flexible Lipid Bilayers in Implicit Solvent. Phys. Rev. E. 2005, 72, 011915. 32 Noguchi, H.; Takasu, M. Self-Assembly of Amphiphiles into Vesicles: A Brownian Dynamics Simulation. Phys. Rev. E. 2001, 64, 041913. 33 Katsov, K.; Mueller, M.; Schick, M. Field Theoretic Study of Bilayer Membrane Fusion I Hemifusion Mechanism. Biophys. J. 2004, 87, 3277. 34 May, S.; Kozlovsky, Y.; Ben-Shaul, A.; Kozlov, M.M. Tilt Modulus of a Lipid Monolayer. Eur. Phys. J. E. 2004, 14, 299–308. 35 Ginzburg, V.V.; Balijepalli, S. Modelling the Thermodynamics of the Interaction of Nanoparticles with Cell Membranes. Nano Lett. 2007, 7, 3716–3722. 36 Ayton, G.; Voth, G.A. Bridging Microscopic and Mesoscopic Simulations of Lipid Bilayers. Biophys. J. 2002, 83, 3357–3370. 37 Wang, Z.-J.; Deserno, M. A Systematically Coarse-Grained Solvent-Free Model for Quantitative Phospholipid Bilayer Simulations. J. Phys. Chem. B 2010, 114, 11207. 38 Ge, Z.; Li, Q.; Wang, Yi. Free Energy Calculation of Nanodiamond-Membrane AssociationThe Effect of Shape and Surface Functionalization. J. Chem. Theory Comput. 2014, 10, 2751–2758.


33


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 34 of 39

39 Van Lehn, R. C.; Ricci, M.; Silva, P. H.; Andreozzi, P.; Reguera, J.; Voitchovsky, K.; Stellacci, F.; Alexander-Katz, A. Lipid Tail Protrusions Mediate the Insertion of Nanoparticles into Model Cell Membranes. Nat. Commun. 2014, 5, 4482. 40 Wong-Ekkabut, J.; Baoukina, S.; Triampo, W.; Tang, I. M.; Tieleman, D. P.; Monticelli, L. Computer Simulation Study of Fullerene Translocation through Lipid Membranes. Nat. Nanotechnol. 2008, 3, 363–368. 41 Li, Y.; Chen, X.; Gu, N. Computational Investigation of Interaction between Nanoparticles and Membranes: Hydrophobic/Hydrophilic Effect. J. Phys. Chem. B 2008, 112, 16647– 16653. 42 Huang, C.; Zhang, Y.; Yuan, H.; Gao, H.; Zhang, S. Role of Nanoparticle Geometry in Endocytosis: Laying Down to Stand Up. Nano Lett. 2013, 13, 4546–4550. 43 Shi, X.; von dem Bussche, A.; Hurt, R. H.; Kane, A. B.; Gao, H. Cell Entry of OneDimensional Nanomaterials Occurs by Tip Recognition and Rotation. Nat. Nanotechnol.

2011, 6, 714–719. 44 Curtis, E.M.; Bahrami, A.H.; Weikl, T.R.; Hall, C.K. Modeling Nanoparticle Wrapping or Translocation in Bilayer Membranes. Nanoscale 2015, 7, 14505–14514. 45 Haugen, A.; May, S. The Influence of Zwitterionic Lipids on the Electrostatic Adsorption of Macroions onto Mixed Lipid Membranes. J. Chem. Phys. 2007, 127, 215104. 46 Reynwar, B.J.; Illya, G.; Harmandaris, V.A.; Müller, M.M; Kremer, K.; Deserno, M. Aggregation and Vesiculation of Membrane Proteins by Curvature-Mediated Interactions. Nature 2007, 447, 461–464. 47 Harries, D.; Ben-Shaul, A.; Szleifer, I. Enveloping of Charged Proteins by Lipid Bilayers. J. Phys. Chem. B 2004, 108, 1491–1496.


34

Page 35 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


48 Faraudo, J.; Martin-Molina, A. Competing Forces in the Interaction of Polyelectrolytes with Charged Interfaces. Curr Opin Colloid Interface Sci 2013, 18, 517–523. 49 Spangler, E.J.; Upreti, S.; Laradji, M. Partial Wrapping and Spontaneous Endocytosis of Spherical Nanoparticles by Tensionless Lipid Membranes. J. Chem. Phys. 2016, 144, 044901. 50 Goetz, R.; Lipowsky, R. Computer Simulations of Bilayer Membranes: Self-Assembly and Interfacial Tension. J. Chem. Phys. 1998, 108, 7397. 51 Goetz, R.; Gompper, G.; Lipowsky, R. Mobilitiy and Elasticity of Self-Assembled Membranes. Phys. Rev. Lett. 1999, 82, 221. 52 Brannigan, G.; Philips, P.F.; Brown, F.L.H. Flexible Lipid Bilayers in Implicit Solvent. Phys. Rev. E 2005, 72, 011915. 53 Spangler, E.J.; Kumar, P.B.S.; Laradji, M. Anomalous Freezing Behavior of Nanoscale Liposomes. Soft Matter 2012, 8, 10896–10904. 54 Cooke, I.R.; Kremer, K.; Deserno, M. Tunable Generic Model for Fluid Bilayer Membranes. Phys. Rev. E 2005, 72, 011506. 55 Hömberg, M.; Müller, M. Main Phase Transition in Lipid Bilayers: Phase Coexistence and Line Tension in a Soft, Solvent-Free, Coarse-Grained Model. J. Chem. Phys. 2010, 132, 155104. 56 Aydin, F.; Dutt, M. Bioinspired Vesicles Encompassing Two-Tail Phospholipids: SelfAssembly and Phase Segregation via Implicit Solvent Coarse-Grained Molecular Dynamics. J. Phys. Chem. B 2014, 118, 8614–8623. 57 Langer, R. Perspectives: Drug Delivery – Drugs on Target. Science 2001, 293, 58–59.


35


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 36 of 39

58 Venkataraman, S.; Hedrick, J. L.; Ong, Z. Y.; Chuan, Y.; Ee, P. L. R.; Hammond, P. T.; Yang, Y. Y. The Effects of Polymeric Nanostructure Shape on Drug Delivery. Advanced Drug Delivery Reviews 2011, 63, 1228–1246. 59 Eniola, A.; Hammer, D. Artificial Polymeric Cells for Targeted Drug Delivery. J Control Release 2003, 87, 15–22. 60 Frenkel, D.; Smit, B. Understanding Molecular Simulations: From Algorithms to Applications; Academic Press: San Diego, 2002. 61 Leach, A.R. Molecular Modeling Principles and Applications; Addison Wesley Longman: Essex, England, 1996. 62 Allen,

M.P.;

Tildesley,

D.J.

Computer

Simulations

of

Liquids;

Clarendon Press: Oxford, 2001. 63 Plimpton, S. Fast Parallel Algorithms for Short-Range Molecular Dynamics. J Comp Phys

1995, 117, 1–19. 64 Imura, T.; Sakai, H.; Yamauchi, H,; Kaise, C.; Kozawa, K.; Yokoyama, S.; Abe, M. Preparation of Liposomes Containing Ceramide 3 and Their Membrane Characteristics. Colloids and Surf B Biointerfaces 2001, 20, 1–8. 65 Chan, E.R.; Ho, L.C.; Glotzer, S.C. Computer Simulations of Block Copolymer Tethered Nanoparticle Self-Assembly. J. Chem. Phys. 2006, 125, 064905. 66 Kiselev, V. Y.; Marenduzzo, D.; Goryachev, A.B. Lateral Dynamics of Proteins with Polybasic Domain on Anionic Membranes: A Dynamic Monte-Carlo Study. Biophys. J.

2011, 100, 1261–1270. 67 de Graaf, J.; Boon, N.; Dijkstra, M.; van Roij, R. Electrostatic Interactions between Janus Particles. J. Chem. Phys. 2012, 137, 104910.


36

Page 37 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


68 Mbamala, E.C.; Fahr, A.; May, S. Electrostatic Model for Mixed Cationic-Zwitterionic Lipid Bilayers. Langmuir 2006, 22, 5129–5136. 69 Tzlil, S.; Murray, D.; Ben-Shaul, A. The “Electrostatic-Switch” Mechanism: Monte Carlo Study of MARCKS-Membrane Interaction. Biophys J. 2008, 95, 1745–1757. 70 Beard, D.A.; Schlick, T. Computational Modeling Predicts the Structure and Dynamics of Chromatin Fiber. Structure 2001, 9, 105–114. 71 Kim, Y.C.; Hummer, G. Coarse-Grained Models for Simulations of Multiprotein Complexes: Application to Ubiquitin Binding. J Mol Biol. 2008, 375, 1416–1433. 72 Jusufi, A.; Hynninen, A.-P.; Haataja, M.; Panagiotopoulos, A.Z. Electrostatic Screening and Charge Correlation Effects in Micellization of Ionic Surfactants. J. Phys. Chem. B 2009, 113, 6314–6320. 73 Kremer, K.; Grest, G.S. Dynamics of Entangled Linear Polymer Melts: A Molecular‐ dynamics Simulation. J. Chem. Phys. 1990, 92, 5057. 74 Pozzi, D.; Colapicchioni, V.; Caracciolo, G.; Piovesana, S.; Capriotti, A. L.; Palchetti, S.; de Grossi, S.; Riccioli, A.; Amenitsch, H.; Lagana, A. Effect of Polyethyleneglycol (PEG) Chain Length on the Bio-Nano-Interactions between PEGylated Lipid Nanoparticles and Biological Fluids: From Nanostructure to Uptake in Cancer Cells. Nanoscale 2014, 6, 2782– 2792. 75 Song,

Y.;

Chen,

S.

Janus

Nanoparticles:

Preparation,

Characterization,

and

Applications. Chem. Asian J. 2014, 9, 418–430. 76 Li, Y.; Gu, N. Thermodynamics of Charged Nanoparticle Adsorption on Charge-Neutral Membranes: A Simulation Study. J. Phys. Chem. B 2010, 114, 2749–2754.


37


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 38 of 39

77 Zhang, L.F.; Granick, S. How to Stabilize Phospholipid Liposomes (Using Nanoparticles). Nano Lett 2006, 6, 694–698. 78 Pera, H.; Nolte, T.M.; Leermakers, F.A.M.; Kleijn, J.M. Coverage and Disruption of Phospholipid Membranes by Oxide Nanoparticles. Langmuir 2014, 30, 14581–14590. 79 Paloncýová, M.; Vávrová, K.; Sovová, Ž.; DeVane, R.; Otyepka, M.; Berka, K. Structural Changes in Ceramide Bilayers Rationalize Increased Permeation through Stratum Corneum Models with Shorter Acyl Tails. J. Phys. Chem. B 2015, 119, 9811–9819. 80 Nagle, J. F.; Tristram-Nagle, S. Structure of Lipid Bilayers. Biochim. Biophys. Acta 2000, 1469, 159. 81 Leonenko, Z.V.; Finot, E.; Ma, H.; Dahms, T.E.S.; Cramb, D.T. Investigation of Temperature-Induced Phase Transitions in DOPC and DPPC Phospholipid Bilayers Using Temperature-Controlled Scanning Force Microscopy. Biophys. J. 2004, 86, 3783–3793.


38

Page 39 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table of Contents Image


39

Surface Reconfiguration of Binary Lipid Vesicles via Electrostatically

Recommend Documents