Cation-Size-Dependent DNA Adsorption Kinetics and Packing Density

Article pubs.acs.org/Langmuir

Cation-Size-Dependent DNA Adsorption Kinetics and Packing Density on Gold Nanoparticles: An Opposite Trend Biwu Liu, Erin Y. Kelly, and Juewen Liu* Department of Chemistry, Waterloo Institute for Nanotechnology University of Waterloo, Waterloo, Ontario, Canada N2L 3G1 S Supporting Information *

ABSTRACT: The property of DNA is strongly influenced by counterions. Packing a dense layer of DNA onto a gold nanoparticle (AuNP) generates an interesting colloidal system with many novel physical properties such as a sharp melting transition, protection of DNA against nucleases, and enhanced complementary DNA binding affinity. In this work, the effect of monovalent cation size is studied. First, for free AuNPs without DNA, larger group 1A cations are more efficient in inducing their aggregation. The same trend is observed with group 2A metals using AuNPs capped by various self-assembled monolayers. After establishing the salt range to maintain AuNP stability, the DNA adsorption kinetics is also found to be faster with the larger Cs+ compared to the smaller Li+. This is attributed to the easier dehydration of Cs+, and dehydrated Cs+ might condense on the AuNP surface to reduce the electrostatic repulsion effectively. However, after a long incubation time with a high salt concentration, Li+ allows ∼30% more DNA packing compared to Cs+. Therefore, Li+ is more effective in reducing the charge repulsion among DNA, and Cs+ is more effective in screening the AuNP surface charge. This work suggests that physicochemical information at the bio/nanointerface can be obtained by using counterions as probes.

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proportional to the final salt concentration.19 Other factors, such as the pH and surfactant, can influence the kinetics and capacity of DNA loading as well.20,21 At the same time, the dense DNA layer attracts counterions to produce a high local salt concentration, which is directly responsible for the sharp melting transition and elevated melting temperature for DNAlinked AuNPs.22 The immobilized DNA is protected against nuclease degradation, which is attributed to the inactivation of the enzyme by the high local Na+ concentration.23 So far, NaCl has been the most commonly used salt. We reason that at the crowded AuNP/DNA interface, the size of counterions might play a critical role in determining DNA packing, thus influencing the conjugate property. Therefore, in addition to their charge, the cation size needs to be considered as well. Herein, we study DNA adsorption kinetics, AuNP aggregation, and DNA loading density with group 1A cations from Li+ to Cs+. Interestingly, cations that promote faster initial DNA adsorption result in a lower DNA packing density. Our work suggests that these cations can be used as a probe at bio/ nano interfaces.

INTRODUCTION Because DNA is a polyelectrolyte, counterions play a critical role in affecting its structure and property. Changing cation species and concentrations modulate important DNA properties such as the melting temperature (Tm), conformation, and chemical functions (e.g., metal binding and DNAzyme activity).1 A further level of complexity arises when DNA is densely immobilized on a surface to form a polyelectrolyte corona. DNA-functionalized gold nanoparticles (AuNPs) are such an example, which have become a cornerstone in nanotechnology with a broad range of applications including biosensor development,2−7 drug delivery,8,9 and directed assembly of materials.10−14 A key feature of this conjugate is an extremely high DNA density, which is partially enabled by the high radii of curvature of small AuNPs. For example, DNA on a 10 nm AuNP is ∼4 times more dense than on a planar gold surface.15 This dense layer of highly negatively charged DNA generates a number of important physicochemical and biochemical consequences.16 First, because of both steric and charge stabilization, this conjugate has high colloidal stability. In addition, this conjugate binds to its complementary DNA (cDNA) orders of magnitude more tightly compared to the affinity achieved by free DNA.17,18 Finally, the melting transition is also much sharper than the melting of free DNA. These properties are also related to counterions. In fact, immobilizing thiolated DNA on AuNPs relies on a process called salt aging, where NaCl is gradually added to the mixture of DNA and AuNPs over 1 to 2 days. The final DNA density is © 2014 American Chemical Society

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MATERIALS AND METHODS

Chemicals. All of the DNA samples were purchased from Integrated DNA Technologies (IDT, Coralville, IA). The sequence of DNA1 is SH-5′-A9CCCAGGTTCTCT-FAM (FAM = carboxyReceived: April 28, 2014 Revised: October 14, 2014 Published: October 20, 2014 13228

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Figure 1. Photographs of citrate-capped 13 nm AuNPs in the presence of various concentrations of (A) monovalent and (B) divalent chloride salts. (C) MPA-capped and (D) MCSA-capped 13 nm AuNPs in the presence of various concentrations of divalent metal ions. Dispersed AuNPs are red, but a purple or blue color indicates AuNP aggregation. fluorescein). Citrate-capped 13-nm-diameter AuNPs were prepared following literature methods, and the product concentration was ∼10 nM.24 PEG 20 000 was from VWR, and mercaptosuccinic acid (MCSA), 3-mercaptopropionic acid (MPA), and all of the monovalent and divalent salts (chlorides) were from Sigma-Aldrich. The DNAs used for Tm measurement were 5′-TCACAGATGCGT-AlexaFluor488 and Iowa Black FQ-5′-ACGCATCTGTGA, forming a duplex. AuNP Aggregation. A final concentration of 5 nM citrate-capped AuNPs was used, and the metal salts were quickly mixed to induce aggregation. After 1 h, the color of the AuNPs was recorded using a digital camera. To prepare SAM-capped AuNPs, 10 nM AuNPs were mixed with 0.1 mM thiol compounds. Divalent metal salts were studied in a similar way. DNA Adsorption Kinetics. To study the effect of monovalent ions on the adsorption kinetics, 10 nM DNA1 was dissolved in 90 μL of HEPES buffer (5 mM, pH 7.6) containing various salts (LiCl, NaCl, KCl, RbCl, CsCl, 150 mM) and 2% PEG 20 000. The fluorescence intensity at 535 nm (excitation at 485 nm) was monitored for 2 min using a microplate reader (Infinite F200Pro, Tecan). AuNPs were incubated with 2% PEG 20 000 overnight. After a quick addition of 10 μL of AuNPs-PEG solution (DNA/AuNP = 10:1), the fluorescence was monitored for another 20 min. In another experiment, 1 nM DNA1 was dissolved in 90 μL of the same HEPES buffer containing varying salts (32 mM LiCl or 30 mM LiCl with 2 mM CsCl). Then citrate-capped AuNPs (no PEG treatment) were added to induce DNA adsorption. DNA Adsorption Capacity. To measure the adsorption capacity, DNA1 was loaded onto AuNPs using the salt-aging method.24 In brief, AuNPs were first incubated with 3 μM DNA overnight (DNA/AuNP = 300:1), and then the pH was adjusted by HEPES (final concentration = 5 mM). The salt concentrations were gradually increased to 100 or 300 mM with various monovalent salts over 10 h. After overnight incubation, the AuNPs were centrifuged (15 min, 21 130g), and the supernatant was removed. Then the AuNPs were washed with HEPES (pH 7.6, 5 mM) four times and dispersed in the

HEPES buffer. The amount of adsorbed DNA was determined by fluorescence measurement after dissolving the AuNPs with 10 mM KCN. All of the experiments were run in triplicate, and the error bars represent the standard deviation. Tm Measurement. The fluorophore-labeled DNA (5 μM) and quencher-labeled DNA (6 μM) were first hybridized in 100 mM HEPES (pH 7.6). The final test solution contained 5 mM HEPES after diluting the hybridized DNA, and the final fluorophore-labeled DNA concentration was 250 nM. Various concentrations of monovalent salts were added. Fifteen microliters of the sample was transferred to a PCR plate, and the plate was sealed. The melting curves were collected using a real-time PCR thermocycler (CFX96, Bio-Rad) with a heated lid. The fluorescence in the FAM channel was measured after a holding time of 20 s at each temperature with a 1 °C increment.

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RESULTS AND DISCUSSION Salt-Induced AuNP Aggregation. To achieve reproducible DNA attachment, it is important to ensure the colloidal stability of AuNPs during an experiment. Citrate-capped AuNPs (13 nm, see Figure S1 for TEM) were used, and they were stabilized only by the electrostatic repulsion from weakly adsorbed citrate. Because AuNPs experience a much larger attractive van der Waals (vdW) force than do most other nanoparticles (e.g., ∼90 times larger than polystyrene particles of the same size),25 AuNPs are easily aggregated by adding just a low concentration of salt to screen the charge repulsion. Therefore, we first need to establish the concentration limit of each salt. The aggregation of AuNPs can be conveniently monitored using UV−vis spectroscopy or visual inspection. Dispersed AuNPs are red, and aggregated ones are purple or blue. According to DLVO theory, these monovalent salts should have the same charge screening power. Interestingly, we 13229

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to that of citrate-capped AuNPs (Figure 1B). With MCSA, which has two carboxyl groups (Figure 1D), the stability was even lower. For example, 0.1 mM Ba2+ induced full aggregation of 10 nM AuNPs in Figure 1D, where each AuNP allocated only ∼10 000 Ba2+ ions. Because this number is not too far away from the number of surface gold atoms, it strongly indicates that the cations are condensed close to the AuNP surface instead of dispersed following the Poisson−Boltzmann distribution. Such direct ion binding is very efficient for charge screening (e.g., the concept of the Stern layer). It appears that larger cations bring a significant potential drop within the Stern layer. Because the divalent ions show the same trend as the monovalent ions in all cases, the hypothesis of Cs+ directly adsorbing onto the AuNP surface is supported. Further evidence comes from the DNA adsorption studies described below. Kinetics of DNA Adsorption as a Function of Cation Size. After understanding the colloidal stability of AuNPs in each type of salt, we next studied the kinetics of DNA adsorption. Thiolated DNA adsorption by gold follows a twostep process.19 First, at low DNA density, the attached DNA tends to lie flat on the surface because DNA bases also have a strong affinity for gold (although not as strong as thiol). The main repulsive force for this stage is the charge repulsion between DNA and AuNPs. With increasing DNA concentration enabled by adding more salt, the adsorbed bases are gradually displaced by thiol to force the DNA into an upright conformation. Counterions play two roles in this process: (1) screening charge repulsion between DNA and AuNPs and (2) screening charge repulsion among immobilized DNA. At high DNA density, repulsion among DNA is more important. Therefore, we measure two parameters to reflect these two roles of counterions. The first parameter is the initial adsorption kinetics, which is measured by fluorescence quenching of a FAM-labeled DNA at low DNA concentrations. The second parameter is the final DNA loading capacity after

observed that larger cations are much more effective at inducing AuNP aggregation, where a color change to blue was observed with just 10 mM CsCl (Figure 1A). However, the AuNPs remained stably dispersed even in 50 mM LiCl. Similar observations were also made with divalent metal ions (Figure 1B), where 0.3 mM Ba2+ induced aggregation, but the particles were stable in the same concentration of Mg2+. At first glance, an easy explanation is the Hofmeister series. Cs+ is higher on the list than Li+, meaning that Cs+ is more effective in precipitating negatively charged proteins. However, we do not believe that this is directly applicable to this study because the highest salt concentration we used was ∼100 mM. Cs+ induced aggregation at ∼10 mM (Figure 1A), and Ba2+ induced aggregation below 0.3 mM (Figure 1B). With such low ionic strength, the main effect of salt should be ionic (e.g., charge screening) instead of hydrophobic to explain the Hofmeister series.26−29 Our data indicate that large cations are better at screening charge repulsion among AuNPs. With the same charge, larger cations have a lower charge density and are less hydrated or more easily dehydrated than smaller ones (Table 1). This might Table 1. Size of the Cationsa ion b

R (nm) Rh (nm)c a

Li+

Na+

K+

Rb+

Cs+

0.07 0.34

0.102 0.276

0.138 0.232

0.149 0.228

0.170 0.226

Data taken from ref 35. bR = ionic radius. cRh = hydrated ion radius.

allow the larger cations to bind directly to an AuNP surface through inner sphere interactions.30−32 To test this hypothesis further, we treated our AuNPs with small thiol compounds to form self-assembled monolayers (SAM). Carboxyl groups are known to have a strong affinity for divalent cations. When capped with MPA, which contains a single carboxyl group (Figure 1C), the AuNPs’ stability slightly decreased compared

Figure 2. Kinetics of (A) FAM-A15 and (C) DNA1 (FAM and thiolated dual-labeled) adsorption as a function of cation size (150 mM) in 2% PEG 20 000. Kinetics of (B) FAM-A15 and (D) DNA1 adsorption in 32 mM Li+ or 2 mM Cs+ with 30 mM Li+. The decrease in fluorescence intensity indicates DNA adsorption. 13230

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salt aging with a high concentration of DNA and salt over a long time, where the system is approaching thermodynamic equilibrium. To measure the initial adsorption kinetics, FAM-labeled DNA and 13 nm AuNPs were mixed in a ratio of 10:1. To maintain AuNP stability, the salt concentration should be limited to ∼5 mM on the basis of our data in Figure 1A. However, this ionic strength is too low to adsorb DNA. To solve this problem, we included 2% polyethylene glycol (PEG, molecular weight = 20 000) to increase the AuNP stability through depletion stabilization,33,34 where no aggregation was observed with even 150 mM salt. To measure the initial adsorption kinetics, we employed two types of FAM-labeled DNA. First, a nonthiolated FAM-A15 DNA (i.e., 15-mer adenine homopolymer) was tested (Figure 2A). Because AuNPs strongly quench fluorescence, DNA adsorption is monitored by the fluorescence change. The adsorption kinetics of FAM-A15 is similar in the presence of Li+, Na+, and K+. The adsorption rate is significantly faster with Rb+ and Cs+. In particular, when Cs+ is compared to Li+, a very large difference is observed. As a control, DNA was tested in the absence of added salt (Figure 2A, black trace), where the signal remained stable. PEG does not significantly change the hydrodynamic size of AuNPs (Figure S2A), suggesting that PEG has little interaction with the gold surface. If any adsorption takes place, PEG is likely to wrap like a chain, instead of maintaining its global structure.34 To eliminate artifacts that might be caused by PEG, we also compared adsorption kinetics in the presence of either 32 mM Li+ or 30 mM Li+ plus 2 mM Cs+ so that the total ionic strength is the same (Figure 2B). Note that the citrate-capped AuNPs are stable in 30 mM Li+. DNA attachment is still faster for the Cs+-containing sample. Such a large kinetic difference from just 2 mM Cs+ in a background of 30 mM Li+ strongly suggests specific interactions between Cs+ and the AuNP surface. To test the generality of this observation, we next repeated the same experiments with a thiolated and FAM-labeled DNA. Attaching this DNA has increased the hydrodynamic size of AuNPs (Figure S2B). The overall adsorption kinetics are much faster because of the presence of the thiol label (Figure 2C,D). Li+, Na+, and K+ still resulted in a similar rate of DNA adsorption, and Rb+ and Cs+ were progressively faster. With PEG (Figure 2C), the first-order rate in the presence of Cs+ is 2.5-fold that in Li+. Without PEG (Figure 2D), the rate is 34% faster with Cs+. These experiments indicate that Cs+ is more effective not only in inducing AuNP aggregation but also for the attachment of DNA to AuNPs. The origin of these properties should be the same (i.e., Cs+ is more effective in screening the charged AuNPs). A scheme showing this comparison is in Figure 3A. On the basis of the kinetic results, one might expect that the final DNA loading capacity is also higher with Cs+. However, as shown below, the opposite was observed. DNA Adsorption Capacity as a Function of Cation Size. Next, we carried out the standard salt aging protocol to immobilize a high density of DNA on the AuNPs (initial DNA/ AuNP = 300:1). The DNA density results are plotted in Figure 4A, where the final salt concentration was 100 or 300 mM. For each cation, the final DNA density was higher with a higher salt concentration, consistent with previous reports using NaCl.19 At each ionic strength, the density of DNA was the highest with Li+, and it progressively dropped with increasing cation size. The density was ∼30% higher with Li+ compared to that with

Figure 3. (A) Scheme explaining how AuNPs initially adsorb DNA faster in the presence of large cations. Because Cs+ can be more easily dehydrated and directly adsorb onto the particle surface, it more effective screens long-ranged electrostatic repulsion. Li+ is more hydrated and cannot easily reach the particle surface and its charge repulsion is less effective. (B) The final density of DNA is higher with small cations because of their thermodynamically stronger interaction with DNA and smaller geometric size that allows for a higher DNA packing density. In other words, Li+ interacts more strongly with DNA and Cs+ interacts more strongly with AuNPs.

Cs+. It is interesting that this loading capacity trend is reversed from the initial adsorption kinetics. At first glance, this is consistent with Li+ being the smallest ion, and thus it allows for packing more DNA. It is important to note that because Li+ has the highest charge density it actually has the largest hydrated size (Table 1). Therefore, these counterions are likely to at least partially dehydrate nearby DNA to account for our DNA density results. To test this hypothesis, we assume a simple model that in the close-packed state n DNA molecules surround each AuNP (cross-sectional area of DNA = AD) and each DNA has m salt ions (not shared; cross-sectional area =AS). The total cross-sectional area should add up to the surface area of the AuNP of 615 nm2 (assuming a radius of 7 nm by considering the spacer due to the alkyl-thiol chain between DNA and the gold surface and all of the space on the gold is occupied by either DNA or cations); that is, 615 = n(AD + mAs). We plotted 615/n as a function of As in Figure 4C and obtained AD = 3.6 nm2 and m = 13.5 by linear fitting. A double-stranded DNA has a cross section area of ∼3.2 nm2, and this is similar to the number from our model using ss-DNA. Because our calculation is based on a 2D cross-sectional shell, each DNA can contribute only one negative charge. Therefore, it is unlikely that 13.5 cations can be packed around that negative charge. In other words, it is unlikely that the size difference between Li+ and Cs+ can account for the 30% difference in DNA loading capacity. Because the size of the cations alone cannot explain the difference in DNA loading, another possibility is that the effective size of DNA is influenced. For example, DNA molecules might be packed more closely to each other in the presence of Li+. At high DNA density, the main repulsion force against further DNA loading should be from DNA−DNA interaction. We suspect that Li+ is better at screening the charge repulsion among DNA strands and allows DNA to be packed more closely. The affinity between monovalent cations and DNA has been studied by a number of techniques including electrophoresis,36 NMR,37,38 atomic force microscopy,39 and electrochemistry,40 but the results are not consistent. Herein, we measured the Tm of a 12-mer DNA (Figure 4D). Li+ has the highest Tm in all tested concentrations. Therefore, Li+ is a better DNA binder and may afford closer DNA packing.41 This is consistent with the higher final DNA density, which should be a thermodynamic measurement. The change in ζ-potential as a function of salt concentration for thiolated DNA-capped AuNPs was also measured in the presence of Li+ and Cs+ 13231

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Figure 4. (A) DNA loading density (number of DNA molecules on each AuNP) after salt aging with a final salt concentration of 100 or 300 mM. (B) DNA loading density with a mixture of Li+ and Cs+ but keeping the total ionic strength 300 mM. (C) Estimation of DNA size and the number of counterions for each DNA based on the data in (A) using a simple geometric model. (D) Tm of a duplex DNA as a function of cation concentration and size.

Finally, we re-emphasize that our conditions for measuring the initial adsorption kinetics and the final DNA loading were quite different. The initial adsorption kinetics were measured at low salt concentration (e.g., 32 mM ionic strength, or 150 mM with PEG). The final capacity was measured at a much higher salt concentration (300 mM). To bridge the gap in salt concentration in our experiment, we also measured DNA loading in the presence of PEG with 150 or 300 mM NaCl. In both cases, Li+ still produced a higher final loading than Cs+ (Figure S4). This further supports that the final DNA loading and initial adsorption kinetics follow opposite trends.

(Figure S3). The effect was quite similar at low salt concentration, but with greater than 100 mM salt, Li+ showed a slightly stronger effect in suppressing the surface charge, which is also consistent with its stronger DNA binding property. Because it took ∼2 days for the salt aging experiment, the density of DNA in the presence of Li+ must have caught up gradually. For the initial DNA adsorption kinetic measurement, charge screening on AuNPs appears to be important. For the final loading capacity, the screening of DNA repulsion is more important (Figure 3B). It needs to be noted that with 100 and 300 mM NaCl, the loading of DNA decreases almost linearly from Li+ to Cs+, but the Tm difference is quite small from Na+ to Cs+ (i.e., Li+ is significantly higher than the rest). Therefore, Tm may not completely reflect all of the factors related to DNA loading. Other factors such as the cation size and DNA dehydration might also contribute. Because the AuNP concentration is ∼10 nM, 100 μM counterions are sufficient to compensate for all of the DNA charges at the interface. An interesting experiment is DNA loading in a mixture of Li+ and Cs+ while keeping the total ionic strength the same. As shown in Figure 4B, ∼100 mM Li+ is needed to achieve a high density of DNA. Therefore, the thermodynamic driving force for DNA loading is not high enough to compensate for the entropic loss of enriching the ions at the interface at very low Li+ concentrations. Note that the capacity measurement has ∼20% inconsistency for experiments carried out on different days. Such measurements are quite complex, containing multiple solution transfer and washing steps and calibration curves. The inconsistency might be related to pipetting errors, washing inconsistency, photobleaching, and timing. Therefore, it is more informative to compare the trend in loading capacity change in each experiment rather than the absolute values.

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CONCLUSIONS We studied the effect of monovalent cations in inducing AuNP aggregation and the kinetics and loading capacity of DNA adsorption by AuNPs. A number of interesting observations have been made in this work. (1) Negatively charged AuNPs aggregate more easily in the presence of larger cations. This happens at very low salt concentrations for AuNPs and is attributed to larger cations being more easily dehydrated to adsorb directly in the Stern layer on the particle surface as shown in Figure 3A. The same trend is also observed for the initial attachment of DNA to AuNPs. (2) Despite the initial DNA attachment kinetics being slower, smaller cations yield a higher final DNA density on AuNPs. This could be a useful method for further fine tuning the DNA density on AuNPs (e.g., started with the same initial DNA concentration but varying added salt). It appears that larger cations are better at screening the AuNP surface charge but smaller cations are better at reducing electrostatic repulsion among DNA molecules. (3) From the pure colloidal science perspective, studying AuNPs allows us to do research in a low salt concentration region that is not accessible with many other types of particles. Most other types of colloids require much 13232

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higher salt concentrations to aggregate, but AuNPs are aggregated at low millimolar salt concentrations.

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ASSOCIATED CONTENT

* Supporting Information S

TEM, ζ-potential, DLS, and additional DNA loading data. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Funding for this work is from the University of Waterloo, the Canadian Foundation for Innovation, the NSERC of Canada, and the Early Researcher Award from the Ontario Ministry of Research and Innovation.

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REFERENCES

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dx.doi.org/10.1021/la503188h | Langmuir 2014, 30, 13228−13234