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Cite this:Phys.Chem.Chem.Phys.,

2014, 16, 3909

Interaction between functionalized goldnanoparticles in physiological saline†

Shada A. Alsharif, Liao Y. Chen,* Alfredo Tlahuice-Flores, Robert L. Whetten andMiguel Jose Yacaman

The interactions between functionalized noble-metal particles in an

aqueous solution are central to applications relying on controlled

equilibrium association. Herein, we obtain the potentials of mean

force (PMF) for pair-interactions between functionalized gold

nanoparticles (AuNPs) in physiological saline. These results are

based upon >1000 ns experiments in silico of all-atom model

systems under equilibrium and non-equilibrium conditions. Four

types of functionalization are built by coating each globular Au144

cluster with 60 thiolate groups: GS–AuNP (glutathionate), PhS–AuNP

(thiophenol), CyS–AuNP (cysteinyl), and p-APhS–AuNP ( para-amino-

thiophenol), which are, respectively, negatively charged, hydrophobic

(neutral-nonpolar), hydrophilic (neutral-polar), and positively charged

at neutral pH. The results confirm the behavior expected of neutral

(hydrophilic or hydrophobic) particles in a dilute aqueous environ-

ment, however the PMF curves demonstrate that the charged AuNPs

interact with one another in a unique way—mediated by H2O mole-

cules and an electrolyte (Na+, Cl�)—in a physiological environment. In

the case of two GS–AuNPs, the excess, neutralizing Na+ ions form a

mobile (or ‘dynamic’) cloud of enhanced concentration between the

like-charged GS–AuNPs, inducing a moderate attraction (B25 kT)

between them. Furthermore, to a lesser degree, for a pair of p-APhS–

AuNPs, the excess, neutralizing Cl� ions (less mobile than Na+) also

form a cloud of higher concentration between the two like-charged

p-APhS–AuNPs, inducing weaker yet significant attractions (B12 kT).

On combining one GS– with one p-APhS–AuNP, the direct, attractive

Coulombic force is completely screened out while the solvation

effects give rise to moderate repulsion between the two unlike-

charged AuNPs.

Due to their intermediacy in size, nanoparticles (NPs) possessunique mesoscopic properties that neither microscopic normacroscopic bodies have. They are therefore widely investi-gated for various purposes, for example, NPs have been studied

in the pursuit of nanomedicine.1–7 In particular, gold nanoparticles(AuNPs) are being exploited for drug delivery and bioimaging,8–15

which can involve solutions with high concentrations of AuNPsand the controlled, reversible association of NPs.16 In light ofthe current studies, it is of essential relevance to accuratelydetermine the interactions between functionalized AuNPs in anaqueous environment, approximating physiological conditions.While in vitro and in vivo experiments have the final say, in silicostudies, complementing in vitro/vivo experiments, can giveatomistic insights to details that cannot be gained by in vitro/vivo means alone. For example, in silico experiments17–20 havebeen employed to study the diffusion of functionalized AuNPsand to study how an AuNP interacts with biomolecules and cellmembranes.21–28 In this paper, we present in silico studies ofAuNPs coated with hydrophobic, neutral hydrophilic, positivelycharged, and negatively charged organic/biological groups,that lead to the determination of AuNP–AuNP interactions inphysiological saline. The AuNP size selected has been usedcontinuously in biological investigations over the past decade.29,30

Our main objective is to elucidate the atomistic details of howfunctionalized AuNPs interact with one another under near-physiological conditions.

It is interesting to note that our in silico study of all-atommodels concludes that like-charged AuNPs in physiologicalsaline significantly attract one another over a distance of a fewtimes the NP diameter. This counter-intuitive behavior is in linewith the long-studied attractions between like-charged colloids inelectrolyte solutions.31–57 However, oppositely charged colloidshave been rarely studied.58

We study five atomistic model systems (see Table 1) eachwith a pair of AuNPs in a box of physiological saline (150 mMNaCl; 1 bar; 298 K). An example is shown in Fig. 1. A singleglobular AuNP comprises a compact 144-atom metal coreprotected by a surface layer of 60 thiolate groups (shown inFig. 2): either the negatively charged tripeptide L-glutathionates(GS–), the hydrophobic thiophenols (PhS–), the hydrophilic(neutral but polar) amino-acid L-cysteinates (CyS–), or the positivelycharged aminothiophenols (p-APhS–). The ligand structures are

Department of Physics and Astronomy, University of Texas at San Antonio,

One UTSA Circle, San Antonio, TX 78249, USA. E-mail: Liao.Chen@utsa.edu

† Electronic supplementary information (ESI) available: Computational details.See DOI: 10.1039/c3cp54503b

Received 24th October 2013,Accepted 25th November 2013

DOI: 10.1039/c3cp54503b

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illustrated in the ESI† (Fig. S1). The atomic structure of theinorganic core, including the sulfur–gold bonding, was takenfrom ref. 59–61. System I consists of two GS–AuNPs; system II,two PhS–AuNPs; system III; two CyS–AuNPs; system IV, twop-APhS–AuNPs; system V, one GS–AuNP and one p-APhS–AuNP.All share a common diameter of 2.0 nm (enclosing the inorganiccore Au144S60).

All the inter- and intra-molecular (other than Au–Au andS–Au) interactions were represented with the CHARMM36 forcefield,62,63 to which we add the following van der Waals (vdW)parameters for Au: s = 1.66 Å, e = �0.10585 kcal mol�1. Waterwas represented with the TIP3P model.64 Parameters for theinteractions involving sulfur and gold atoms were taken fromref. 65. The in silico experiments, namely, molecular dynamics(MD) simulations, were implemented using NAMD66 as adaptedfor steered molecular dynamics (SMD).67,68 Periodic boundaryconditions were applied in all dimensions. The cut-off distanceapplied to the vdW interactions was 1.2 nm, with a switchingdistance of 1.0 nm and a pair list distance of 1.4 nm. Particle-meshEwald was employed to compute the electrostatic interactions inan exact manner. Langevin MD was implemented with a time-step

of 1.0 fs for short range interactions and 4.0 fs for long rangeinteractions. The Langevin damping was chosen as 5.0 ps�1.The temperature was maintained at T = 298 K and pressure at1.0 bar.

The building procedure of system I is summarized asfollows: (1) starting from the widely accepted59–61 structure ofthe Au144(SR)60 cluster, [R = H or CH3] we built a GS–AuNP bybonding one moiety (HS-less glutathione) to each of the 60 Satoms on the surface of the cluster. The mutual spatial arrange-ments of the 60 glutathionate groups were attained by mini-mizing the interaction energy of the GS–AuNP while fixing thecoordinates of all the Au and S atoms to their initial values.Then we let the GS–AuNP equilibrate for 100 ns at 298 K undervacuum, first with the Au and S constrained, and then foranother 100 ns, without constraints on any of the atoms. Itshould be noted that the Au–S core was found to be stable,preserving the icosahedral symmetry, which indicates thevalidity of the interaction parameters we used. (2) We replicatedthe GS–AuNP and placed two of them in a box of water. We thenneutralized the system with 120 Na+ ions and salinatedthe system with 150 mM NaCl. The procedures for buildingsystems II–V are essentially identical to those for system I and,therefore, not explicitly stated here. Some details are providedin the ESI† (Fig. S2 and S3).

Equilibrium molecular dynamics

Following initial optimizations, we executed 100 ns equilibriumMD runs for each system. During the last 50 ns of the MD run,we computed the root-mean-square-deviation of the 144-Auatoms from their initial structure (excluding the overall diffusionand rotation of the NP) to check the validity of the interactionparameters we used. Note that none of the atoms were fixed orconstrained during the equilibrium MD run. All atoms were

Table 1 Details of the systems considered in this study

System NP1 charge NP2 charge InteractionRange ofattraction (nm)

I GS–AuNP GS–AuNP �25kT 3.7 to 4�60e �60e

II PhS–AuNP PhS–AuNP �15kT 2.7 to 40e 0e

III CyS–AuNP CyS–AuNP Repulsive0e 0e

IV p-APhS–AuNP p-APhS–AuNP �12kT 3 to 3.7+60e +60e

V p-APhS–AuNP GS–AuNP Repulsive+60e �60e

Fig. 1 The in silico box of physiological saline with two AuNPseach coated with 60 glutathiones. The system dimensions are 10 nm �10 nm � 20 nm, consisting of 191 355 atoms. The water molecules are inlicorice (sticks) and the NPs and ions are in VDW (balls) representationsrespectively. (Na+, yellow, Cl�, gray-blue, O, red, C, cyan, N, blue, and H,white). Au and S are not visible in this figure. All graphics in this paper wererendered with VMD.69

Fig. 2 144-AuNPs coated with 60 aminothiophenols (top left), glutathiones(top right), cysteines (bottom left), and thiophenols (bottom right). Gold andsulphur atoms are in VDW representation (large spheres) in gold and lightyellow colors respectively. The ligands are in CPK (ball-and-stick) representa-tions (O, red, C, cyan, N, blue, and H, white).

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freely subject to the stochastic dynamics on the basis of atomisticinteractions of the system modeled by the CHARMM36 force field.

Non-equilibrium steered moleculardynamics

We followed the multi-sectional scheme of ref. 70, conductingSMD runs for each of the systems I–V in order to compute thePMF71–76 as a function of the distance r between the centres-of-mass of the pairs of AuNPs. In each case, we steered (pulled) thepair of AuNPs toward each other at the same pulling speed nd =1.0 nm ns�1 in every case. The pulling was along the z-axis andover sections of 0.1 nm. Namely, the center-of-mass (COM)coordinates of the innermost 12-Au core (three degrees offreedom) were controlled as functions (0, 0, zi � ndt) of time talong a forward–reverse pulling path in the ith section while allother 0.57 million degrees of freedom were left freely deter-mined by the stochastic dynamics of the system. Here zi and zi+1

are, respectively, the z-coordinates of the two end points ofthe i th section over which we pulled the centre-of-mass of theinner Au core forward and backward to sample four (eight insome cases) forward–reverse pulling paths in each given section.The work done to the system, along these pulling paths (shownin ESI† Fig. S5–S9), was used in the Brownian-dynamicsfluctuation-dissipation theorem77 to compute the free-energydifference (reversible work or PMF) as a function of the distance,i.e. the pairwise separation of AuNPs. Namely, the free-energydifference between two states:

GðzÞ � G zAð Þ ¼ �kBT lnexp �WA!Z=2kBT½ �h iFexp �WZ!A=2kBT½ �h iR

� �: (1)

Here WA-B is the work done to the system along a forward pathwhen the NP pair was steered from A to Z. WZ-A = WB-A�WB-Z

is the work for the part of a reverse path when the NP pair waspulled from Z to A. kB is the Boltzmann constant and T is theabsolute temperature. zA and zB are the z-coordinates of the COMof one of the two NPs of the pair at the end states A and B of thesystem, respectively. Note that the pulling was symmetricalbetween the two NPs of each pair.

Stability of the globular inorganic Au144S60 core was clearlyestablished in all five cases. None of the four different surfactantshad a substantial effect on the arrangement, as the icosahedralsymmetry is maintained, including the 30-fold Au–S–Au–S–Au staplegeometry. Fig. S4 (ESI†) shows quantitatively that the rms-deviation(from the initial Au-atom coordinates) remains within 0.02 nm,confirming the validity of the parameters used to characterize theAu–S and Au–Au interactions, which are not part of the standardCHARMM36 force field.

Our main finding is that the like-charged AuNPs in physiologicalsaline do not repel but rather attract one another, via electrolyte ion-mediated attractions, starting from distances around a few timesthe AuNP diameter. Fig. 3 shows the PMF between two negativelycharged GS–AuNPs (�60e charge each), and similarly the PMFbetween two positively charged p-APhS–AuNPs (+60e charge each).These PMF curves establish that the direct Coulombic repulsion

between two like-charged AuNPs is very effectively screened by thephysiological saline that provides 120 extra counter-ions (120 Na+

ions, for GS–AuNPs; 120 Cl� ions, for p-APhS–AuNPs). Some of thecounter-ions reside at the surface of these AuNPs, as illustrated inFig. 4, reducing its effective charge to a small fraction of 60e. Thefree counter-ions (those not residing at the AuNP surfaces) gather inbetween the two like-charged AuNPs, as much as electrons gather inbetween the two protons of an H2 molecule (on the Å length-scale),mediating attraction between two like-charged AuNPs.

The origin of the difference between the GS–AuNP pair andthe p-APhS–AuNP pair, as indicated in Fig. 4, is that the Cl�

ions are less mobile than Na+ ions and, therefore, are moreeffective in neutralizing the positively charged p-APhS–AuNP.This implies a reduced effective charge in p-APhS–AuNP, versusGS–AuNP. Consequently, the attraction between p-APhS–AuNPsis weaker than that between GS–AuNPs. Note that the distancescorresponding to the minima of the PMFs for both like-chargedparticle pairs in Fig. 3 coincide with 2 times the distancescorresponding to the maxima of the surrounding charge densitiesin Fig. 4.

By contrast, oppositely-charged AuNPs in physiological salinedo not attract one another. The PMF for the unlike-charged pairof AuNPs is also shown in Fig. 3, which clearly indicates a small

Fig. 3 The reversible work for bringing two NPs together. Vertical axis:potential of mean force. Horizontal axis: distance between the centers-of-mass of the two NPs involved.

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but significant effective repulsion between the two. In this case,the direct Coulombic attraction, between a positively chargedp-APhS–AuNP and a negatively charged GS–AuNP (see ESI†Fig. S10), is totally screened out. Instead, the long-range inter-action between them is repulsive due to the solvation effects.78

Fig. 3 further shows that the neutral hydrophilic AuNPs—thePMF is for a pair of such AuNPs, CyS–AuNPs—tend to separatefrom one another. This behaviour is easily rationalized in termsof the drive to maximize the total area exposed to aqueoussolution.

Finally, the neutral hydrophobic AuNPs tends to coagulatetogether. Fig. 3 also shows the PMF for a pair of (neutral)thiophenol-coated AuNPs, indicating the long range and deep,broad free-energy minimum associated with the classic hydro-phobic effect, i.e. the reduction in the total (non-polar) surface-area exposed to aqueous solution.78

Conclusions

Extensive atomistic in silico experiments (equilibrium MD andnon-equilibrium SMD simulations), based on realistic molecularstructures for all solution components, lead to the conclusion thatthe interactions between functionalized AuNPs in physiologicalsaline are fundamentally distinct compared to under vacuum andother environments. On the length-scale of a few times the AuNPdiameter, the direct Coulombic interactions are completelyscreened out. Like-charged AuNPs do not repel and opposite-charged AuNPs do not attract one another. The water moleculesand the Na+ and Cl� ions play essential roles to mediate theeffective attractions between a pair of like-charged AuNPs (positiveor negative) as well as a pair of hydrophobic AuNPs. This fact alsoexplains the experimental observation that thiol passivated AuNPsare stable for a long time in sharp contrast with nonpassivatedparticles. Solvation effects cause both the opposite-charged pairand the neutral–hydrophilic pair to dissociate. These predictedcharacteristics of various functionalized AuNPs are expected toimpact further research of AuNPs in biological applications.

The authors are indebted for the support from the followingfunding agencies: the NIH (Grants #GM084834 and #G12RR013646),

the Welch Foundation (Project AX-1615), and the NSF (Grants#DMR-0934218 and #1103730). They also acknowledge thecomputational support from the Texas Advanced ComputingCentre and the NSF XSEDE (TG-MCB130070).

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