Characterizing DNA Corona Rigidity in DNA-Directed Gold

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Characterizing DNA Corona Rigidity in DNAdirected Gold Nanoparticle Crystalline Structures Ha Youn Lee, Casey Ren, and Sung Yong Park J. Phys. Chem. C, Just Accepted Manuscript • DOI: 10.1021/acs.jpcc.6b05396 • Publication Date (Web): 25 Jul 2016 Downloaded from http://pubs.acs.org on August 10, 2016

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The Journal of Physical Chemistry

Characterizing DNA Corona Rigidity in DNAdirected Gold Nanoparticle Crystalline Structures Ha Youn Lee, Casey Ren, and Sung Yong Park* Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, CA 90089, USA

ABSTRACT

DNA-linked gold nanoparticle systems have become an adaptable self-assembly tool to program various crystalline orders.1-6 The programmability lies in the DNA corona7-11, a highly dense outer shell of DNA linkers, that binds the nanoparticles together. Various self-assembled structures can be formed by changing properties of the DNA corona, in particular, the size ratio.3,5 However, there still remains uncertainty as to the actual behavior and structural rigidity of the DNA itself, impeding advances in structural diversification; the per base contribution to the distance between spherical DNA-linked nanoparticles has been reported to be less than the Bform DNA rise of 3.4 Å,3-5,12 suggesting that the DNA may adopt an A-form structure after crystallization.5,12 Alternatively, a more flexible DNA corona could be generated if B-form DNA persists but becomes physically bent and adsorbed to the nanoparticle surface in crystal formations.13,14 To understand the rigidity of the DNA corona, we devised a method to stretch the DNA between two nanoparticles by simultaneously using short and long linkers. This linker

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combination flexibly acts like a single linker, rather than two separate linkers that create two ranges of interactions. By measuring the edge-to-edge distance between the two nanoparticles using both linkers in a small angle X-ray scattering (SAXS) experiment, we recorded the first per base contribution that is consistent with the B-form DNA rise of 3.4 Å. The elucidation of DNA behavior within nanoparticle crystals is essential for understanding the programmability of DNA-linked nanoparticle systems.

INTRODUCTION Linking various DNA strands on nanoparticle surfaces has been a primary focus of DNAguided nanoparticle self-assembly. Tailoring the properties of the DNA corona, particularly the sticky ends and size ratio (the relative size difference between DNA coronas in a binary system), is crucial for creating versatile crystalline orders.1-11 Certain coronal properties such as DNA rigidity need to be fully understood to diversify crystalline structures and improve programmability precision. For instance, if DNA coronas are rigid within crystals, we could produce multiple interaction ranges by using different lengths of DNA linkers, and thus add more diversity to crystalline structures. However, the conformation of the DNA that determines the rigidity of the corona has been difficult to characterize. Several studies reported that the per base contribution, each base’s average length between two spherical nanoparticles, is approximately 2.6 Å.3-5,12 This measurement is considerably smaller than the Watson-Crick Bform DNA rise of 3.4 Å (Figure 1); rather, it is consistent with the A-form DNA rise of 2.6 Å.15 It is unknown whether this reduction is caused by a structural transition, perhaps to the A-form, resulting in a rigid DNA structure (Figure 1C), or by a physical deformation, through adsorption


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onto the nanoparticle surface and strand bending, resulting in a flexible DNA conformation (Figure 1B). The B-form typically predominates in nature, while the A-form is adopted in some nonaqueous conditions or transition states.15-17 In some extreme conditions such as where the salt concentration inside a gold nanoparticle crystal becomes far higher than outside, due to counterion condensation, the structural transition from B-form to A-form could occur. Previous molecular dynamics studies showed that by increasing salt concentration, A-form DNA can be more stable than B-form DNA in the presence of nonaqueous solvent.16,17 Although the mechanisms that lead to the transition between B-form and A-form are not fully clarified, the small energy difference between the two states theoretically implies this transition’s feasibility.16,17 However, a recent molecular dynamics study observed structural transitions from A-form to B-form between gold surfaces.18 An alternative hypothesis is that the diminished per base contribution is due to a physical adsorption and bending of the DNA.13,14 When double stranded DNA is adsorbed or bended, the length of DNA can vary. This flexibility in DNA length indicates the variation in the DNA corona size, resulting in chances in the size ratio. Note that the size ratio is one of the most critical factors for determining crystal types in DNAprogrammable nanoparticle crystallization.5 The current method for assessing the size ratio involves measuring the hydrodynamic radius of individual nanoparticles in suspension.5 However, the size ratio measured using individual nanoparticles in suspension may differ from that within a crystal environment due to interactions between neighboring coronas. This may decrease the accuracy of predicting the self-assembled structure. In this study, we accurately measure the size of DNA coronas using SAXS experiments. To understand the size variation caused by the changes in the system such as internal crystalline


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structure development or temperature, we monitor the annealing process of the system using insitu SAXS experiments. Moreover, this study devises novel experimental schemes which can measure the DNA per base contribution in diverse crystallization settings. One scheme in particular examines whether the DNA has the potential to be fully stretched within a nanoparticle crystal by simultaneously using both long and short linker strands. Our method directly addresses the two hypotheses of either a structural transition in DNA or a physical deformation, which can provide important insight into the factors that control the programmability of crystals.

RESULTS AND DISCUSSION Design of DNA-linked gold nanoparticle systems Oligonucleotides attach to the nanoparticle surface to form a DNA corona, as shown in Figure 2A. The surface DNA (colored blue in Figure 2B) binds directly to the gold nanoparticle via a thiolated 5’ end, and is followed by 10 unpaired adenine bases and an 18 base pair region that is complementary with the linker DNA. The linker DNA (colored black in Figure 2B) contains the region complementary with the surface DNA followed by a spacer and a complementary sticky end that links the two nanoparticles together. The number of bases separating two nanoparticles can be varied with the addition of a spacer in the linker DNA. The spacer either consists of a paired DNA sequence flanked by unpaired adenine flexors on both ends, or a flexible polyethylene glycol (PEG) oligomer (Figure 2B). In this study, we use hexaethylene glycol (PEG6). By annealing these complementary regions under thermodynamically favorable conditions, the DNA-linked gold nanoparticles self-assemble into an ordered nanoparticle crystal.3,5


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Control Experiments using a single-component DNA-linked nanoparticle system We first produced three face-centered cubic (FCC) crystals to use as a reference to predict the effective radii of body-centered cubic (BCC) self-assemblies. These FCC crystals used selfcomplementary sticky ends and surface and linker DNA containing either 11, 22, or 33 bp spacers (Figure 2B). Here, we introduce the effective radius of the DNA corona as a way to accurately predict the size ratio and thus improve the programmability of DNA-linked nanoparticle systems. The effective radius is deemed as each DNA corona’s individual contribution to the interparticle distance within a crystal, which is shown in Figure 2A. The interparticle distance of a crystalline structure is the distance between the centers of two core nanoparticles, which is equivalent to the sum of their effective radii, while the edge-to-edge distance is the shortest linear distance between the surfaces of two connected nanoparticles (Figure 2A). By experimentally measuring the interparticle distance and the core radii, we determine the edge-to-edge distance, which can be used to assess the per base contribution of the DNA by accounting for the number of separating bases. We obtain the interparticle distance, dint , from the FCC structure factor of SAXS experiments as dint = 6π / q0 where q0 is the position of the (111) peak, while the size of the core gold nanoparticles can be accurately estimated by the form factor of the stable DNAlinked nanoparticle suspension. The edge-to-edge distance was measured for each of three FCC crystals and plotted against the number of separating bases (Figure 3 and 4). For all samples, we measure the distance at 45 °C, right below the melting temperature after the annealing is complete. The linear regression yielded a slope of 2.7 Å per base contribution, consistent with previous reports.3-5,12 This value is smaller than the B-DNA rise of 3.4 Å and is close to the A-DNA rise of 2.6 Å. However, the per


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base contribution using one-sample measurement, where we directly estimate the per base contribution of each sample by discounting all other contributing factors, became more close to 3.4 Å, the pitch of B-DNA, especially when using short spacer lengths. The relative measurement method obtaining per base contribution from the linear regression coefficient can be advantageous because it does not require considering other contributing factors. However, it may not avoid systematic complications originating from the bending of duplex due to the interaction between nanoparticles or from the formation of multiple duplex strands between nanoparticles. The bending effect may increase as duplex length increases, and thus it may systematically reduce the interparticle distance14,15. We used the linear regression curve to estimate the contribution of a PEG6 spacer. For this, we produced another FCC crystal using a different type of linker containing a PEG6 molecule instead of an adenine flexor, as shown in Figure 2B. The linear regression from Figure 4 was used to assess the number of bases corresponding to one PEG6 molecule, yielding 3.35 bases. The length of a fully stretched PEG6 molecule was previously reported as 21.0 Å.19 Assuming that PEG6 adopts a DNA conformation with a 5.58 ~ 6.46 Å phosphate-phosphate distance,20 the PEG6 molecule should correspond to 3.25 ~ 3.76 bases within the FCC crystal. This concordance with the linear regression estimate suggests that PEG6’s contribution to the interparticle distance can be well approximated as 3.35 bases.

Accurate measurement of the size of gold nanoparticles using small-angle X-ray scattering The size and size distribution of core nanoparticles in solution can be accurately estimated using SAXS experiments since the major contribution comes from the scattering from core gold nanoparticles. When spherical nanoparticles differing in size are sparsely placed in the sample


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and contribute independently to X-ray scattering, the scattering intensity of the sample is obtained by averaging over the scattering intensity of each particle. When nanoparticles have a size distribution, the scattering intensity is calculated as21,22:

I=

∑I i

N

i

=

I (0) dRR 6 f (R)F(q, R)2 , 6 ∫ R

Eq. (1)

where (̅ 0) is scattering intensity at q=0, (, ) is the form factor of a spherical colloidal particle with radius , and ( ) is the size distribution of particles and R is the average radius of particles. One way to consider the size distribution is to use well-defined analytical functions, such as a Schultz distribution.23 This distribution has two parameters, which are related to the average radius and the root mean square deviation: z

1  z   z  fs (R) =  1  R z1−1 exp  −  1  R  / Γ(z1 ),  R   R 

Eq. (2)

where is a width parameter ( > 0), related to the root mean square deviation of the average radius, which is given by

σ = R / z1 .

Eq. (3)

The scattering intensity with Schultz distribution is written by z1 z1 +2    α   z1 (z1 + 1)   α   −1 2  −1 2   I(q) = I (0)q −6 1−  cos z tan + 1+ cos (z + 2) tan       1 1 2    2   α α α    4 + α 2    4 + α  

−2

 z1  α  α  4 + α 2 

z1 +1

2  sin  (z1 + 1)tan −1   ,  α  

Eq. (4) where = / . The one-dimensional scattering intensity measured in the nanoparticle suspension does fit well with the theoretical scattering intensity, which assumes that nanoparticles are spherical with a


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Schultz distribution. Other distributions such as Gaussian or Log-normal distribution were used to estimate the size and size distribution of nanoparticles, but the estimated value was not significantly dependent on the particular distribution used24. Figure 5 presents the experimental scattering curves of gold nanoparticle suspensions (D = 10 and 15 nm) fitted to the Schultz distribution. The estimated particle size was 10.2 nm ± 0.81 nm for D = 10 nm and 15.5nm ± 1.7nm for D = 15 nm, respectively. The size and the size distribution of nanoparticles were not altered during the synthesis, including the purification procedure (data not shown). The best fit to the scattering curve of D = 10 nm for values of q greater than 0.02 slightly deviates at low q region from the measurement made prior to a separation of sediments through low rpm centrifugation. This indicates that the nanoparticle solution may have contained some nanoparticle aggregates. The putative aggregates were removed from the solution with low rpm centrifugation. This separation step can affect the outcome of DNA modification during the synthesis procedure.

In-situ small-angle X-ray scattering experiment for monitoring the annealing process The interparticle distance in DNA-directed self-assemblies is closely associated with DNA conformation3,12,25, and monitoring the annealing process through an in-situ small-angle X-ray scattering experiment provides valuable information about the interparticle distance and DNA duplex structure in the nanoparticle superlattice. In Figure 6, we present the change of structure factor during the annealing process using DNAlinked nanoparticles (D = 10 nm). Starting at room temperature, we add linker strands with selfcomplementary sticky ends and a 22 base-long spacer. After pre-annealing the sample overnight, we place it in a flow cell and control the temperature through the annealing process. The sample


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initially shows a scattering pattern consistent with that of a disordered structure (i.e. random hexagonal close-packed structure). As the annealing proceeds, the structure noticeably develops and the peak informing the interparticle distance shifts, as shown in Figures 6 and 7. As annealing progresses near the melting temperature, 45 ºC, the sample develops an FCC structure (lower dataset in Figure 6). The first peak initially located at q = 0.0186 Å-1 at 26 ºC moves towards a lower q value, which indicates an increase in the interparticle distance (Figure 7). After we decrease the temperature and maintain the sample for 2 hours at room temperature, we observe that the first peak at 26 ºC ( q = 0.0183 Å-1) is not at the same position we obtained at the beginning of the experiment. This observation suggests that the interparticle distance is dependent on not only the temperature but also the annealing path. As annealing progressed further at 45 ºC, we observe more distinct peaks in the structural factor (4 upper curves in Figure 6). The observed structure development is in concordance with the structure development during the packing simulation where the process of annealing is mimicked by changing the packing density (Figure 8). (The details of the packing simulation are described in the following section.) For example, the peak at q / q0 = 3 can be divided into two peaks at (220) and (311). Also, it is worth noting that some distinct peaks in the perfect FCC structure such as (111), (220), and (311) develop more quickly than others.

Three-dimensional hard-particle packing simulation We conducted three-dimensional hard-particle packing simulations using event-driven molecular dynamics26,27 in order to understand the annealing behavior of DNA-directed nanoparticle crystallization. In this simulation, particles undergo hard collisions as particle size is increased with a given expansion rate, which eventually results in a jamming stage. In addition to


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the particle size expansion rate, the target density is another control parameter. When the expansion rate is high enough, particles will jam into each other before the system reaches the target density, and thus the number of collision events diverges. In the event-based molecular dynamics, the physical time of the simulation starts to slow down near the jamming stage and cannot progress beyond the jamming time point. Due to the huge number of events occurring in a very short time period, the time increment between two adjacent events becomes infinitesimal at the jamming point. Thus, we monitored the system at an equal interval in a logarithmic scale, and when the increment of a system value such as physical time or density became smaller than a certain criterion, we stopped the simulation and used the final configuration and its density as the jamming state and jamming density. Figure 8 plots the jamming density, ρ, against the expansion rate in a packing simulation using 400 particles. The jamming density can vary within a given expansion rate depending on the initial state, and thus we averaged it over 10 samples. As we can expect, the jamming density increases as the expansion rate decreases. The increase in the jamming density can be considered as the increase in the degree of order and structure development, as shown in Figure 9. Comparing the simulated jamming configuration with the structure of nanoparticle assemblies, the more ordered structure that follows annealing can be considered to have developed a greater packing density. The characteristics of structure maturation observed from the simulation, such as uneven peak development, were used to interpret results of the annealing experiment. Here, we calculated the structure factor of nanoparticle assemblies from the packing simulation, applying a simplified Debye formula21,22,

I(q) ≈ I e (0)∑ ∑ ρ k ρ j k

j

sin(qrjk ) qrjk

,

Eq. (5)


10

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where =

is the wave vector, is the scattering angle, is the X-ray wavelength, (or

) is the electron number density at position (or ! ), and is the distance between the position and ! . For spherical nanoparticles in finite-size nanoparticle crystals, the scattering intensity I (q ) can be simply written as, N

N −1 N

i=1

i=1 j=i+1

I(q) = ∑ I i (q) + 2∑ ∑ Fi (q)Fj (q)

sin qrij qrij

,

Eq. (6)

2 where the individual form factor is given by I i (q ) = Fi ( q ) . Assuming the same individual form

factors, the structure factor S ( q ) = I (q ) /( NI i ( q )) is written as,

S (q) = 1 +

2 N

N −1 N

∑∑

sin qrij

i =1 j =i +1

qrij

.

Eq. (7)

Per base contribution in binary DNA-linked nanoparticle systems. Next we studied BCC self-assemblies to test how the per base contribution responds to different crystallization settings. The first crystal utilized the linker set BCC11a and BCCPEG6b, deemed the “short” set (Figure 2C). These linkers contained an 11 bp spacer with an “a” sticky end and a PEG6 molecule with a complementary “b” sticky end, respectively. The second crystal utilized the linker set BCC22c and BCC11d, deemed the “long” set (Figure 2D). These linkers contained a 22 bp spacer with a “c” sticky end and an 11 bp spacer with a complementary “d” sticky end, respectively. Finally, the last crystal utilized both of these sets in tandem, BCC11a/BCC22c and BCCPEG6b/BCC11d (Figure 2E). With an assumption that the DNA corona is rigid, the long and short linker set is designed to control the interaction range such that the interaction range of the long linker set corresponds to the distance to next-nearest neighbor while the range of the short linker set conforms to nearest neighbor in a BCC structure. The introduction of next-nearest neighbor interaction can modify the internal ordering of a BCC structure. Normally, two types of nanoparticles align in a CsCl crystal order (BCC/CsCl) (Figure


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2E). All eight nearest neighbors of each nanoparticle are the opposite nanoparticle type, and thus nanoparticles of each type form a simple cubic lattice separately. With next-nearest neighbor interactions, we can alternate the internal order to a NaTl crystal order (BCC/NaTl), where all particles remain on a BCC lattice but the relative position of each nanoparticle type is changed. As a result, in a BCC/NaTl crystal, nanoparticles of each type form a diamond lattice. We estimated the effective radii when 10 nm and 15 nm nanoparticles were used with the short linker set, BCC11a and BCCPEG6b, as shown in Figure 2C. From the linear regression in Figure 4, the effective radius of the 10 nm gold nanoparticle’s DNA corona is 19.16 nm, while that of the 15 nm is estimated to be 19.13 nm. We predict the formation of a BCC/CsCl crystal based on the estimated 1:1 size ratio and the expectation of only nearest neighbour interactions. As expected, the resulting crystalline structure with the BCC11a/BCCPEG6b short linker set was a BCC/CsCl, as shown in Figure 5A. In this BCC/CsCl crystal, the interparticle distance was measured to be 37.98 nm from the (110) peak position of 0.02026 Å-1 in the SAXS experiment, which was consistent with the sum of the predicted effective radii. The experimental scattering curves of gold nanoparticle suspensions were used to estimate each core nanoparticle’s diameter as 10.2 ± 0.81 nm for D = 10 nm and 15.5 ± 1.7 nm for D = 15 nm (Figure 5). Therefore, the edge-to-edge distance was measured to be 25.13 nm with 79.35 separating bases. Similarly when 10 nm and 15 nm nanoparticles were used with the long linker set, BCC22c and BCC11d (Figure 2d), the interparticle distance was measured to be 43.52 nm from the SAXS experiment (Figure 10), also consistent with the sum of the predicted effective radii, 43.94 nm. Therefore, when we use the short and long linker sets separately, the FCC crystals provide reasonable predictions of the


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effective radii of the BCC crystals. Thus the effective radius is a more useful parameter than the hydrodynamic radius for designing a crystalline structure with a single linker set. We then used the above two short and long linker sets in tandem, BCC11a/BCC22c attached to 10 nm nanoparticles and BCCPEG6b/BCC11d attached to 15 nm (Figure 2E). In this case each nanoparticle is predicted to have two effective radii: 19.16 nm for the BCC11a linker and 22.12 nm for the BCC22c linker in the 10 nm nanoparticle, and 19.13 nm for the BCCPEG6b linker and 21.82 nm for the BCC11d linker in the 15 nm nanoparticle. The presence of two effective radii for each nanoparticle would lead to a predicted two shell structure resulting in next nearest neighbor interactions in addition to nearest neighbor interactions to form a BCC/NaTl crystal.7 However, contrary to this expectation, the crystalline structure produced using the short and long linker sets was a BCC/CsCl crystal, as shown in Figure 10A and D. The interparticle distance of the resulting BCC/CsCl crystal structure is 41.8 nm. Interestingly, this distance is neither consistent with the sum of the short effective radii nor the long effective radii, but rather, it is in-between the two sums. Our observations demonstrate that the interparticle distance is not solely determined by the linker length but also influenced by the DNA linker combination. If the change of DNA conformation inside nanoparticle crystals can be described only by the structural transition from B-form to A-form, there would be only be two possible interparticle distances between the nearest neighbor pairs. The two interparticle distances can represent the thermodynamic phases. However, using the short and long linker sets together, the behavior of long linker set cannot not be described with the sole structural transition, since the length of long linker set gets even shorter than previously estimated. On the other hands, in the view of physical deformation, the situation can be easily described, since the tension applied between each DNA strand can adjust the degree of the physical deformation of the DNA


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strand. Moreover, as shown in Figure 11, the melting of the short linker set occurred first and thus resulted in the recovery of the interparticle distance associated with only the long linker set (43.52 nm). In this Figure, we present the change of scattering intensity during the melting process of BCC/CsCl crystals using 10 nm and 15 nm gold nanoparticles with the short linker set, BCC11a and BCCPEG6b, and the long linker set, BCC22c and BCC11d, together. As the temperature is increased, the (110) peak of the BCC/CsCl crystal is shifted to the position corresponding to BCC/CsCl crystals formed using only the long linker set. After the peak shift, all the peaks become smaller, indicating that the nanoparticle crystals have melted completely. When the temperature is decreased to 34.9 ºC after the melting of both linker sets, the original peak at time t=10 min is recovered (Figure 11). All these observations can be easily explained when we assume that melting of the short linker set occurred first, followed by melting of the long linker set. Moreover, as determined below, the short linker set should be fully stretched, and thus it is plausible that the extra tension induced by the long linker set can enhance the dissociation of the short linker set. As a result, the melting of the short linker set can occur first. This observation strongly signifies that the DNA configuration within DNA-linked nanoparticle crystals can vary with experimental conditions. From the measured interparticle distance of 41.8 nm of the BCC/CsCl crystal with the short and long linkers together, the edge-to-edge distance was measured to be 28.95 nm when we subtract the two core nanoparticles’ radii of 5.1 and 7.75 nm. The contribution of each thiol group to the edge-to-edge distance was previously estimated as 0.4 nm.12 The PEG6 molecule in the short linker was assumed to be fully stretched to 2.10 nm.18 By eliminating these extra contributions to the edge-to-edge distance, the net DNA length was estimated as 26.06 nm. Dividing by the 76 bases, total length of the short linker set, the per base contribution was


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calculated as 3.43 Å, which notably corresponds to a B-DNA rise (3.4 Å). This is the first time that consistency with B-DNA rise has been shown for oligonucleotides within any DNA-linked nanoparticle crystal. The resulting increase of the short linker’s per base contribution indicates that the DNA has become fully stretched due to the presence of the long linker. Conversely, the long DNA linker’s per base contribution is reduced from 2.99 Å to 2.82 Å in the presence of the short linker.

CONCLUSIONS In conclusion, we observed that DNA configuration within DNA-linked nanoparticle systems can vary depending on crystal components. In particular, DNA can be fully stretched to be comparable to the B form in a condition in which different lengths of linker sets are used in tandem. The short linker was fully stretched, while the long linker shrank, resulting in only nearest neighbor interactions that led to a BCC/CsCl rather than a BCC/NaTl crystal. Our study offers support for a conformational explanation for the commonly observed shorter per base contribution in nanoparticle crystals. When crystals form, the B-form DNA remains but can be bent and adsorbed to the nanoparticle surface (Figure 1B).13,14 The observed flexible DNA conformation within crystals indicates that the programmability of DNA-linked gold nanoparticle systems should be evaluated with caution. With a more accurate characterization of the behavior of different components of the DNA-linked gold nanoparticle crystals, there is increased design capacity, and in turn, a diversification of function. Nanoparticle crystals have been useful for biochemical sensing due to the color change that is induced by aggregation.1,28 A better understanding of the properties and crystallization conditions of DNA-linked gold


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nanoparticle systems can expand functionality, as evidenced by the increasing interest in nanoparticle drug delivery vehicles.28-30

METHODS Synthesis of DNA-linked nanoparticles All DNA strands were purchased from IDT. Tanic acid capped gold nanoparticles suspended in deionized water were purchased from Ted Pella. All other chemicals, if not specified, were purchased from Sigma-Aldrich. The concentration of unmodified nanoparticles was measured using UV-visible spectroscopy and Beer-Lambert Law. The molar extinction coefficient for gold nanoparticles was referenced from http://www.tedpella.com/gold_html/gold-tec.htm. Small adjustments were made as necessary to accommodate deviation from its listed value. Unmodified gold nanoparticles were functionalized with thiol groups attached at the terminals of DNA strands following a well-documented procedure in Ref. 31 with a few modifications. Terminal dithiol groups attached in surface DNA strands were cleaved using 0.1 M dithiolthreitol (DTT, Thermo Scientific) in 0.2 M phosphate buffer (PB), pH 8.0. A size exclusion column (Illustra NAP-5, GE Healthcare) was used to purify the cleaved DNA strands. After purification, the cleaved DNA strands (more than 2.5 O.D./ml in every effective absorbance 1.0 O.D./ml of a gold nanoparticle solution) were added to a solution of unmodified tanic acid capped gold nanoparticles. Salt aging was used to increase the surface loading of DNA strands. The salt concentration was slowly increased from 0.0 M to 0.5 M for 2 hours by incrementaly adding 2M NaCl, 0.01 M PB, 0.01% sodium dodecyl sulfate (SDS) solution (pH 7.4) every 20 minutes - the resulting salt concentrantion was 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 M in 20 minute intervals. The solution was sonicated for 10 seconds whenever salt was added. Once


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salt aging was complete, the solution was incubated at room temperature for at least overnight, before the removal of excess DNA strands using sequential centrifugation. After purification, the solution was centrifuged at low rpm to remove the sediment. Final nanoparticles were stored in a 0.5M NaCl, 0.01 M PB (pH 7.4), 0.01% SDS solution.

Small-angle X-ray Scattering (SAXS) experiment The SAXS experiments were employed to determine the size and size distribution of core gold nanoparticles and the crystalline structure of DNA-linked nanoassemblies. All SAXS experiments were performed at DND-CAT Sector 5 and BESSRC-CAT Sector 12 of the Advanced Photon Source, Argonne National Laboratory. The scattered beam was monitored with a CCD detector. The one-dimensional profile can be obtained from azimuthal integration of the two-dimensional scattering pattern which was directly obtained from the CCD detector. The one-dimensional profile as a function of the scattering angle can be simply transformed into one as a function of the scattering vector, with a calibration process using a standard silver behenate reference sample or an equivalent. Standard data correction methods including absorption correction and dark current subtraction were used.

FIGURES


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Figure 1. Different DNA conformation scenarios within nanoparticle crystals. The DNA is hybridized to gold nanoparticle cores with a thiol group and consists of surface (blue) and linker (black) DNAs. A. A fully stretched B-DNA within a nanoparticle crystal would make a per base contribution consistent with the B-DNA rise of ~3.4 Å. B. A bent B-DNA within a nanoparticle crystal would result in a per base contribution of ~2.6 Å that is shorter than the B-DNA rise of ~3.4 Å. C. A fully stretched A-DNA would make a per base contribution consistent with the ADNA rise of ~2.6 Å.


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Figure 2. DNA-linked gold nanoparticles and linker sequences. A. Two DNA coronas in a nanoparticle crystal with their effective radii (the distance from the center of the core nanoparticle to half of the linker’s sticky end) summing to the interparticle distance. The edgeto-edge distance is the interparticle distance minus the two nanoparticles’ radii. B. FCC crystals are formed with one type of linker containing a self-complementary sticky end. Four different FCC crystals were created with 11, 22, 33 bp spacers, or a PEG6 molecule. BCC crystals use a binary set of linkers. Three BCC/CsCl crystals were formed with (C) a short linker set (BCC11a/BCCPEG6b), (D) a long linker set (BCC22c/BCC11d), and (E) both short and long linker sets together.


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Figure 3. Structure Factors and two-dimensional SAXS patterns of FCC crystals. A. The structure factors, S(q), of FCC crystals using 10 nm gold nanoparticles with the FCC linker sets in Figure 2B. Four different FCC crystals were created with 11 (blue), 22 (red), 33 (green) bp spacers, or a PEG6 molecule (black) with a self-complementary sticky end. The corresponding two-dimensional SAXS patterns of the FCC assemblies using a FCC linker with PEG6 (B), 11 (C), 22(D), and 33 (E) spacer.


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Figure 4. Edge-to-edge distances of FCC crystals. Edge-to-edge distance was measured as a function of total number of separating base pairs from FCC crystals with 11, 22, and 33 bp spacers (black dots). The dotted line presents the linear regression, and the slope of 2.7 Å represents the relative per base contribution to the edge-to-edge distance between nanoparticles.


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Figure 5. Scattering intensity of gold nanoparticle suspensions (D=10 and 15 nm). The experimental data (red, pink, and light blue) were fitted to theoretical curves from Schultz distributions (blue and black). The scattering intensity I(q) of D=10 nm before centrifugation (red) showed a deviation from the theoretical one (blue), which indicates that the sample before centrifugation contains spontaneous aggregates. However, the data after centrifugation (pink) did not show any deviation, and thus we can consider that the centrifugation can successfully separate unwanted spontaneous aggregates from the gold nanoparticle solution.


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Figure 6. Annealing experiment using in-situ Small-angle X-ray scattering (SAXS). The self-complementary linker strands and D = 10 nm DNA-linked nanoparticles were used.


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Figure 7. Estimating interparticle distances from annealing experiments. Change in interparticle distance (red) and annealing temperature (blue) through the annealing process.


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Figure 8. The jamming density ( ρ ) as a function of expansion rate from three-dimensional hard-particle packing simulations. The expansion rate is an important parameter to control the resulting jamming density in the packing simulation. When the size of the particle is slowly increased with the expansion rate during the simulation, the system eventually becomes jammed and shows more ordered morphology when it reaches a higher jamming density. When the system becomes completely packed, forming a perfectly-ordered close-packed crystalline

( )

structure, the density reaches the maximum value, π / 3 2 ≅ 0.74048 .


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Figure 9. Influence of packing density ( ρ ) on structure development in packing simulations. A. The configurations obtained from three-dimensional hard-particle packing simulations were used to calculate the structure factor S(q) using Eq. (7), as a function of wave vector q. We normalized wave vector using the first peak position q0. As shown in Figure 8, the expansion rate was altered to control the packing density of the simulated final configuration; the slower the expansion rate, the higher the packing density. As the packing density was increased, a more ordered structure was obtained. At ρ=0.646 (grey), the system showed a broad peak at

q / q0 = 3 , which indicates random packing (A typical snapshot shown in B). On the other hand, at ρ=0.685 (red), the system developed peaks consistent with a perfect FCC structure (A typical snapshot shown in C).


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Figure 10. Scattering intensities and two-dimensional SAXS patterns for BCC/CsCl crystals. A. The experimental scattering curves I(q) of BCC/CsCl crystals using 10 nm and 15 nm gold nanoparticles with the short linker set, BCC11a and BCCPEG6b (black), the long linker set, BCC22c and BCC11d (blue), and these short and long linker sets together (red). When the short and long linker sets were used in tandem, the (110) peak of the BCC/CsCl crystal was located in between those of the BCC/CsCl crystals created using the short or long linker set only. The corresponding two-dimensional SAXS patterns of the BCC/CsCl assemblies using 10 nm and 15 nm gold nanoparticles with the short linker set (B), the long linker set (C), and the short and long linker sets together (D).


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Figure 11. Annealing experiments using in-situ Small-angle X-ray scattering (SAXS). The experimental scattering curves I(q) over a range of temperatures of BCC/CsCl crystals formed using 10 nm and 15 nm gold nanoparticles with the short linker set, BCC11a and BCCPEG6b and the long linker set, BCC22c and BCC11d together. As the temperature was increased, the melting of the short linker set occurred first, and the (110) peak of the BCC/CsCl crystal was shifted to the position of the BCC/CsCl crystals formed using the long linker set only. When the temperature was decreased to 34.9 ºC after the melting of both linker sets, the original peak at time t=10 minute was recovered, as marked by the black vertical dotted line.


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ASSOCIATED CONTENT

AUTHOR INFORMATION Corresponding Author *Email: [email protected]. Phone: (323) 442-2077. Fax: (323) 442-1721. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This study was supported by NIH grant R01-AI083115.

We thank Dr. S. Seifert, Dr. S.

Weigand, Dr. J. Lee, Dr. B. Lee, Dr. O.-S. Lee, Dr. G. C. Schatz, Dr. M. Z. Yates, Dr. J. Jung, and Dr. C. A. Mirkin for useful discussions. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC0206CH11357.


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TOC Graphic


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Characterizing DNA Corona Rigidity in DNA-Directed Gold

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