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DNA Binding to the Silica Surface Bobo Shi, Yun Kyung Shin, Ali A. Hassanali, and Sherwin J Singer J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.5b01983 • Publication Date (Web): 12 May 2015 Downloaded from http://pubs.acs.org on May 14, 2015

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The Journal of Physical Chemistry

DNA Binding to the Silica Surface Bobo Shi‡ , Yun Kyung Shin†,a , Ali A. Hassanali‡,b , Sherwin J. Singer†,‡,∗ †Department of Chemistry and Biochemistry and ‡Biophysics Program Ohio State University, Columbus, OH 43210 May 10, 2015

Abstract We investigate the DNA-silica binding mechanism using molecular dynamics simulations. This system is of technological importance, and also of interest to explore how negatively charged DNA can bind to a silica surface, which is also negatively charged at pH values above its isoelectric point near pH 3. We find that the two major binding mechanisms are attractive interactions between DNA phosphate and surface silanol groups and hydrophobic bonding between DNA base and silica hydrophobic region. Umbrella sampling and the Weighted Histogram Analysis Method (WHAM) are used to calculate the free energy surface for detachment of DNA from a binding configuration to a location far from the silica surface. Several factors explain why single-stranded DNA (ssDNA) has been observed to be more strongly attracted to silica than double-stranded (dsDNA): 1) ssDNA is more flexible and therefore able to maximize the number of binding interactions. 2) ssDNA has free unpaired bases to form hydrophobic attachment to silica while dsDNA has to break hydrogen bonds with base partners to get free bases. 3) The linear charge density of dsDNA is twice that of ssDNA. We devise a procedure to approximate the atomic forces between biomolecules and amorphous silica to enable large-scale biomolecule-silica simulations as reported here. Keywords: silica, DNA adsorption, umbrella sampling, simulation

* Corresponding author: Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH 43210 614-292-8909 [email protected] Current address: Department of Mechanical and Nuclear Engineering, Pennsylvania State University, University Park PA 16802 b Current address: International Center for Theoretical Physics, Condensed Matter and Statistical Physics 34151, Trieste, Italy a

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1 Introduction Currently there is great interest in the development of micro- and nano-scale devices for analysis and delivery of bio-molecules.1–6 Moving from the macro- to the micro- and nano-scale provides several advantages: less sample required, greater sensitivity because of increased contact area between analyte solution and device surface, and the possibility of developing portable, or even implantable devices through miniaturization. Silica – amorphous silicon dioxide – is one of the common materials used to fabricate micro- and nano-scale biomedical devices. Some of the benefits of silica include low toxicity of the amorphous oxide,7, 8 cost, and an accumulated expertise in fabrication methods. The latter includes expertise in silicon device fabrication because fluids come in contact with a surface layer of amorphous oxide in silicon-based devices.9–11 Silicon dioxide is the principle component of various materials referred to as “glass,” such as soda lime or borosilicate glass. Hence the behavior of bio-molecules near the amorphous silica surface is of both scientific and technological importance. In this work, we examine the behavior of a DNA oligomer near an amorphous silica surface with a charge density typical of neutral pH. It is known that DNA binds to the silica surface, even though both the silica surface and DNA are negatively charged. DNA binding to silica in the presence of chaotropic salts, such as guanidinium thiocyanate and sodium perchlorate, is a standard purification method.12–18 There are also many reports of DNA binding to silica in the absence of chaotropic slates, and at pH values where the silica surface is negatively charged. In the absence of chaotropic salts, Fujiwara et al. found weak binding of double-stranded DNA to silica under neutral or basic pH values. However the binding increased as the pH was lowered toward the isoelectric point of silica.19 Also, the binding of DNA to silica nanoparticles in a pH 7, salt-free solution was detected by Marcie and Savoie20 via a small change in the intensity and frequency of a Raman spectral band at 1092 cm−1 , which was assigned to the DNA phosphate group. To access the type of interactions likely to occur when DNA interacts with silica, Kwon et al.21 performed atomic force microscope measurements in which the AFM probe was a silica particle and the surface was coated with phosphorylated dextran. At neutral pH, the pull-off force for phosphorylated dextran was 80% that of normal dextran, but still exhibited a measurable attraction. Vandeventer et al.22 monitored bulk found adsorption of DNA to silica particles in the presence and absence of chaotropic salts. Additional experimental evidence for DNA binding to silica

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at neutral pH was recently provided by Vandeventer et al.22 and Smerkova et al.23 Single-stranded DNA is found to bind more strongly than double-stranded DNA to silica,24–26 with appreciable binding at pH values above the isoelectric point of silica up to neutral pH.24, 25 This has been explained by increased opportunity for hydrophobic interactions between the unpaired bases of single-stranded DNA and the silica surface.24–26 In this paper we confirm this mechanism, but suggest additional mechanisms that lead to stronger binding of single-stranded DNA. There are many experiments in which DNA is introduced into silica nanopores, often with the goals of chromatographic separation of different oligomers, furnishing a medium for delivery of DNA, or DNA sequencing. The effect of DNA on the ion current is often the experimental method to track the presence, and ultimately the sequence, of DNA. Viovy,27 Baldessari and Santiago28 Branton et al.29 and Zwolak and Di Ventra30 provide general reviews of progress in electrokinetic separation of biomolecules in nano-channels. Since biomolecules are never far from the surface in nano-pores, a key property is the adsorption/desorption behavior of biomolecules at channel walls, which we explore in this work for DNA/silica systems. The numerous reported observations of DNA in micro- and nano-pores include electrokinetic separation of DNA of different lengths in glass nano-channels,31–33 capillary electrophoresis in silica micro-channels to separate DNA fragments of varying size,34 tracking the distribution of DNA in silica micro-channels under various conditions, including the presence of Poiseuille flow.35 Both increase and decrease of ion current as DNA passes through silica nano-pores has been observed, depending on salt concentration.36 Other experiments probe the diffusivity of DNA in silica slit nano-pores with gap heights between 75 and 545nm,37 and the electrophoretic force on a single DNA molecule passing through a SiO2 /SiN/SiO2 pore.38 Zhang and coworkers39 observed translocation of DNA through cylindrical pores in silica. They found translocation in the direction of EOF for the smallest 9nm diameter pores, while translocation was in the direction of DNA electrophoresis for 75nm diameter pores.40 Pure silica nano-pores have not met with the same degree of success as other inorganic or biological pore structure in constructing potential DNA sequencing devices, but silica has been employed in combination with other materials.40–42 Given the extent of experimental interest in systems involving intimate contact between DNA and silica, theoretical investigations are warranted to provide molecular insight into various outstanding issues, such

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as the mechanism by which negatively charged DNA binds to negatively charged silica, and why singlestranded DNA binds preferentially over double-stranded DNA. To date, there have been some theoretical efforts directed toward DNA in nanochannels, most often using continuum theory43–48 There have been several molecularly detailed simulations of DNA near surfaces, but none with a realistic description of DNA in contact with amorphous silica, as developed in this work. Aksimentiev and co-workers when they studied translocation of DNA in Si3 N4 nanopores.49–52 Luan et al. simulated motion of DNA in a channel with regions of metallic and amorphous SiO2 walls.53–55 However, the SiO2 in contact with water was not hydroxylated and charged, and the DNA restrained from contact with the walls. DNA confined near graphene56 and carbon nanotubes57 have also been explored in molecular simulations. Herein, we describe our efforts to elucidate the DNA-amorphous silica binding mechanism for both double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA). Since there are many important applications where biomolecules interact with amorphous silica, our goal in section 2 was to devise a general procedure to estimate interactions between those biomolecules and a silica surface, which we intend to apply . Then in section 3 we specify the methods used in our molecular dynamics and free energy calculations. Results are presented in section 4, followed by section 5 where discussion and conclusions are given.

2 Interaction model development Our strategy to develop a model for biomolecules at the silica/water interface is to interpolate ab initio quantum chemical results between various probe molecules and silica fragments. We interpolate in two senses. First, like any force field, we assume that parameters for atoms in similar bonding situations are transferable. Secondly, we use standard combining rules58 to infer interactions where we have not generated quantum chemical data. These approximations are in standard use for current force fields,59–61 and can capture qualitative trends for systems that are currently beyond the reach of more rigorous methods. Interactions of probe molecules (Fig. 1) with four fragments from the silica surface (Fig. 2) were investigated. The representative probe molecules contain functional groups often found in biomolecules – methane (CH4 ), methanol (CH3 OH), ammonium (NH+4 ), acetate (CH3 COO− ) and benzene (C6 H6 ) This set of molecules includes non-polar, polar, charged, and aromatic species. Some silica fragments contained no 4


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a dissociated silanol group is exposed to a probe molecule (Fig. 2c), and the largest fragment containing 5 silicon atoms used for benzene as a probe in which two silanol groups interact with the probe (Fig. 2d). All cases contained siloxane bonds in addition to possible silanols or dissociated silanols. It should be noted that in the last fragment, the benzene probe had significant exposure to siloxane groups as well as two silanol groups. All results of ab initio calculations are provided in the Supplementary Information. Table 1: Lennard-Jones potential parameters of siloxane (OX ), silanol (OH ), and dissociated silanol (OM ) oxygens that were optimized to best reproduce ab initio data from fragment calculations. The charge parameters are derived from the BKS potential.69 silica atom types charge (e) σ(Å) ǫ(eV) OX (siloxane) −1.2 3.02 4.691 × 10−2 OH (silanol) −1.2 3.06 9.086 × 10−3 OM (dissociated silanol) −1.6 2.95 2.352 × 10−2 Si 2.4 – 0 H (silanol) 0.6 0 0 Using a set of Lennard-Jones parameters for the interaction potential between like atoms, we employed the Lorentz-Berthelot combination rules58 to generate Lennard-Jones parameters for unlike atom pairs.

σi j =

1 √ σii + σ j j , ǫi j = ǫii ǫ j j 2

(1)

In Eq. (1), σii , σ j j , ǫii , ǫ j j are like-atom Lennard-Jones parameters which are used to estimate σi j , ǫi j , the unlike-atom parameters. Our strategy is to parametrize the interaction model with like-atom Lennard-Jones parameters for siloxane (OX ), silanol (OH ), and dissociated silanol (OM ) atom types, and take analogous likeatom Lennard-Jones parameters for biomolecule atom types from available force fields. The full interaction potential is then generated with the combining rules. We optimized Lennard-Jones parameters for the three atom types of the silica surface (OX ,OH ,OM ) other than silicon to achieve a best fit to the ab initio data when using Lorentz-Berthelot combining rules.58 Details are given in the Supplementary Information, and the resulting parameters are summarized in Table 1.

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3 Simulation procedures The DL POLY simulation package70–72 was used to equilibrate the silica slab. All other simulations were performed with the GROMACS program version 4.5.5.73 Interactions within DNA and with water were described with the AMBER99sb force field,74, 75 originally based on the ffamber port to GROMACS76, 77 and now a standard part of GROMACS. A double-stranded DNA with the sequence d(CGCGAATTCGCG)·d(CGCGAATTCGCG), the Drew-Dickerson dodecamer,78 and a single-stranded DNA with the sequence (CGCGAATTCGCG) were used in the simulations. The amorphous silica was made from cycle I-IV of Huff and co-workers.79 To generate the silica slab, the periodic simulation cell was lengthened in one direction, cleaving the silica and introducing an empty region. The exposed silica surface was subsequently annealed, hydroxylated by replacing 2M rings to vicinal silanols and nonbrigding oxygen atoms (NBOs) to geminal silanol pairs, and re-annealed as described in ref. 67. Simulations were conducted using SPC/E water model, and equilibrated after introduction of water. Each simulation is performed in a 7.96nm × 8.61nm × 9.74nm box, the long dimension perpendicular to the silica surface. There are 1611416333 water molecules in the box and 130 (119) sodium ions which neutralize the ds-DNA (ss-DNA) and silica. The number of water molecules was adjusted to achieve a mass density of 1.0g cm−3 in the channel region. The thickness of the silica wall is about 2.7nm and the height of the channel is about 7.0nm. The Lennard-Jones potential parameters for sodium ions are from AMBER99sb force field.74, 75

ssDNA dsDNA

binding events 7 8

phosphate 19 11

binding sites base (hydrophobic) deoxyribose sugar 7 4 1 1

Table 2: Binding statistics for 8 independent simulations for a ssDNA oligomer, 8 independent simulations for a dsDNA oligomer. All of the dsDNA simulations resulted in binding to an undissociated silica surface, while 7 of the 8 ssDNA runs led to binding.

Neutral silica surfaces with no dissociated silanols were employed to construct initial bound configurations. For both dsDNA and ssDNA, 8 simulations, each of length 30ns, were performed in which DNA was introduced 7Å from one of the neutral silica surfaces with axis parallel to the surface. After evolving in time for 30ns, all of the 8 dsDNA simulations, and 7 out of 8 ssDNA simulations were closely associated with the surface. The prevalence of binding modes, which are discussed in detail in section 4, are summarized in 7



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Table 2. The number of binding sites in each event ranged from one to seven. In experimental situations, the silica surface charge density depends on solution pH and electrolyte concentration.80, 81 Since most experiments are conducted near neutral pH, we studied a surface with a charge density of −0.126C/m2 , typical of the neutral range.82 Our silica slab was dissociated by deleting the proton of randomly chosen silanol groups. Then the same number of sodium ions were added to make the system neutral. Several binding configurations were chosen for detailed analysis. They were further equilibrated on the dissociated silica surface for 10ns. In all cases, the DNA oligomer remained bound after charging the surface, although in some cases the bound state was metastable. In the discussion section, we argue this likely underestimates the degree of DNA binding to negatively charged silica. The binding free energy was calculated by umbrella sampling83 combined with the weighted histogram analysis method (WHAM).84–87 A series of simulation windows centered about steadily increasing distances between the binding group, such as phosphate groups or bases, and surface were performed. The umbrella potentials were based on a reaction coordinate which was the distance from the center of mass of the detaching group, either a phosphate or a base, and a silicon atom directly under the group in the bound configuration. In some cases, histograms involving two reaction coordinates were accumulated. When the oligomer is close to its relaxed binding position, the interaction with the silica surface is strong. Hence, a high spring force constant was used to influence the DNA in the presence of strong interactions near the surface. A sharp position distribution is generated by a high spring constant, so the distance between window centers was small near the silica surface. Alternatively, when the oligomer is far from its binding position, the interaction between DNA and silica surface is weaker. A weaker spring force constant is enough to influence the DNA, which gives wider position distribution. The distance between window centers was allowed to grow with increasing distance from the surface. Distance between windows and force constants are included in the supporting information. The configuration obtained at the end of window i was used as the starting point for the next window i + 1. Each window was equilibrated for 1ns and then data was collected for another 1ns. During the sampling of each window, the values of reaction coordinate r, generally the distance between a point on the DNA and another point on the surface, were obtained in order to generate (b) (b) a biased probability histogram, P(b) i (r) in window i. We verified that for all windows i, Pi (r) and Pi+1 (r),

histograms for adjacent windows, had significant overlap. 8


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Following the WHAM procedure,84–87 the biased probability histograms were combined to obtain the unbiased probability.

P(r) = C

X i

P

j nj

ni P(b) i (r) −β(w (r)− f ) j j e

(2)

In the above equation, wi is the biasing potential, ni is the simulation length in window i, and fi is the free energy difference between ith biased system and unbiased system. The fi are obtained by iteratively solving the following self-consistency condition.

e−β fk = C

Z

dr e−βwk (r)

X i

ni P(b) i (r) P

j n je

−β[w j (r)− f j ]

.

(3)

In this equation the integration over r is replaced by a sum over histogram elements. The reaction cooridnate r usually stands for a single variable, but in two cases we studied hydrophobic base-silica interaction using 2D umbrella sampling.

4 Results

Figure 3: A phosphate of a dsDNA is bound to two silanol groups of the silica surface. This binding configuration corresponds to the curve labeled dsDNA1 in Fig. 4. The inset in the lower left is an expanded view of the phosphatesilanol interaction site, where the two silanols interacting with a phosphate oxygen are indicated with a dashed line.

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4.1

Phosphate-silanol interaction

For both dsDNA and ssDNA, we frequently observed phosphate groups of the DNA binding to one or two silanols on the silica surface, as shown in Fig. 3. Umbrella sampling and WHAM provided the the free energy profiles in Fig. 4 for five cases of phosphate-silanol binding. The reaction coordinate was the distance from the phosphate center of mass to a silicon atom directly beneath it in the bound configuration. In all but the run labeled ssDNA2, the phosphate-silanol bond was located toward one end of the oligomer, while the other end of the DNA was sufficiently far from the surface so that it was not interacting. As the biasing potential was changed, both ends of the oligomer moved out of interaction range with the surface. Therefore, pulling apart the phosphate-silanol bond provided an estimate of the overall free energy surface for binding via a single phosphate-silanol bond. In two cases, labeled dsDNA1 and ssDNA1 in Fig. 4, a single phosphate oxygen was in close proximity to two silanol groups. To confirm that the entire range of interaction was included in Fig. 4, we extended the umbrella sampling range, this time adding a biasing potential to two sites to keep the oligomer parallel to the surface. Over an extended range which was 0.5nm more than the range shown in Fig. 4, we observed no change in the free energy. The two dsDNA cases shown in Fig. 4, dsDNA1 and dsDNA2, where binding occurred at just a single phosphate-silanol site, were converted into ssDNA1 and ssDNA3, respectively, by removal of the chain that did not participate in binding with the surface. The free energy profile for binding was re-determined for the remaining chain using umbrella sampling and WHAM. Thus the pairs, dsDNA1-ssDNA1 and dsDNA2ssDNA3, furnish a direct comparison of binding of double- and single-stranded DNA with other factors held nearly the same. The run labeled ssDNA2 in Fig. 4 was somewhat different than the rest. In this run, the ssDNA was attached to the surface by two phosphate silanol interactions, one at the 4th nucleotide from the 3′ end, and another phosphate at the 5′ end. The ssDNA2 curve in Fig. 4 is the free energy to break the phosphate silanol interaction at the 4th nucleotide while the chain remained bound to the surface at the 5′ end. In the bound state, the phosphate-surface distance, as described in the preceding paragraph, was 0.42 to 0.46nm from the surface. Out until 0.54nm from the surface, specific attractive interactions between the phosphate groups and surface contribute strongly to the free energy surface. In the range between 0.55nm

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from the center of mass of the phosphate group to a silicon lying directly below it, not the closest approach between atoms of the phosphate and the silica surface.) While the repulsive portion of the free energy surfaces in Fig. 4 are quite similar among the ssDNA and dsDNA groups, the overall binding free energy varies for different binding locations. Each phosphate has a binding free energy in the range of +20kJ mol−1 (metastable binding) to −41kJ mol−1 . Here the terms stable and metastable are used to distinguish when the bound configuration lies lower or higher in free energy, as compared with the free DNA oligomer. Of course, a dynamic equilibrium between bound and unbound DNA will exist, as directly observed, for example, by Kang et al.24 More precisely, stability or metastability predicts the relative amount of bound and unbound DNA. Three factors cause the large range of overall binding free energy: First, because phosphate location is constrained by its position in the DNA polymer, an individual phosphate oxygen may not be able to achieve its most favorable configuration relative to its silanol bonding partner. Second, the local charge distribution of the silica surface near the binding sites may affect the binding free energy. If there are more negatively charged sites around the binding site, the binding is weaker. For example, the phosphate-silanol binding site of ssDNA3 in Fig. 4 lies close to four dissociated silanol groups that provide negative charge around the binding site. As a consequence, this is the one instance of ssDNA for which binding is metastable. Finally, the inherent differences between ssDNA and dsDNA produce a range of binding energies. ssDNA tends to give stronger binding than dsDNA because ssDNA is more flexible and able to optimize its interactions with the surface, and because the more negatively charged dsDNA produces greater electrostatic repulsion to silica surface than ssDNA. Using B3LYP quantum chemical methods, two groups have estimated the binding energy of a phosphate group to an uncharged silica fragment. Murashov and Leszczynski calculated the gas phase binding energies of an orthosilicic acid unit and either a phosphate or dimethyl phosphate ion.89 They found an average binding energy of 59kJ mol−1 per phosphate-silanol bond. Kwon et al. calculated the binding enthalpy of methyl glucosidic phosphate to an octa-hydroxy silsesquioxane fragment. They obtained a binding enthapy of −129kJ mol−1 for a fragment with two phosphate-silanol bonds (along with other interactions which are much weaker).21 Again, the gas phase binding energy came out to roughly −60kJ mol−1 . These sets of

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results compare nicely with the largest drop in free energy from the maximum near 0.55nm to the bottom of the well observed in Fig. 4. The quantum chemical calculations21, 89 discussed above employed a neutral silica fragment. Therefore, the presence of nearby negative charges on the silica and on the DNA can lessen the magnitude of the binding energy.

4.2

Hydrophobic bonding

Bases of both single stranded DNA (ssDNA) and double stranded DNA (dsDNA) exhibit a tendency to lay adjacent to regions of the silica surface which, because of natural statistical variations, are depleted of silanol groups. We have previously shown that such silanol-free regions of the silica surface are hydrophobic, i.e. that the density of water near these regions is less than the bulk density, and considerably less than the water density near silanol groups.67 The hydrophobic behavior of regions lacking silanol groups was verified by ab initio molecular dynamics simulations.68

(a)

(b)

Figure 5: Guanine and a cytosine of ssDNA oligomer bound to hydrophobic regions of silica surface. (a) and (b) are the same picture but DNA is invisible in (b). Larger red surface atoms are dissociated silanols and white dots are hydrogen atoms. In both snapshots, water and counter-ions are not shown.

Fig. 5 shows an example of ssDNA binding to silica via hydrophobic interactions. Two adjacent bases, guanine and cytosine, were in contact with the silica surface, facing regions depleted of silanol groups. In the figures, a dashed line indicates the binding region. Figs. 5(a) and 5(b) show the same physical configuration. 13



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Water and ions are left out of the picture in Fig. 5(a), and additionally the DNA is not depicted in Fig. 5(b), allowing one to see that the binding regions are depleted of silanol groups. Fig. 6 shows an example of hydrophobic binding of dsDNA. In the double-stranded case, the hydrophobic interaction requires a base to break its hydrogen bonds with its complement, incurring a free energy cost that is not present in the single-stranded case. In our studies, we only observed the end base pair of dsDNA breaking apart to enable hydrophobic interaction with the surface.

(a)

(b)

Figure 6: A cytosine of dsDNA is bound to hydrophobic region of silica surface. (a) and (b) are the same picture but DNA is invisible in (b). Large red spheres are dissociated silanols and white dots are hydrogen atoms.

(a)

(b)

Figure 7: Hydrogen bonding between bases and silica surface concurrent with hydrophobic interactions. (a) Hydrogen bonding between oxygen atom on cytosine and hydrogen atom on silanol group. (b) Hydrogen bonding between NH2 on cytosine and oxygen on silanol group.

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In most cases, concurrent with hydrophobic binding, some hydrogen bonds are formed between bases and the silica surface at the edge of the hydrophobic region. Fig. 7(a) shows a hydrogen bond between the oxygen atom of a hydrophobically bound cytosine from ssDNA and the hydrogen of a silanol group. Simultaneous hydrophobic attraction and hydrogen bonding at the periphery is possible via a ketone oxygen for G, C and T, and via an -NH or NH2 group for all bases, provided the hydrophobic site contains the required hydrogen bonding sites on its periphery. Fig. 7(b) shows a hydrogen bonding between the NH2 group on a cytosine and oxygen on a silanol group. Adenine and guanine also contain a NH2 group, and may engage in simultaneous hydrophobic/hydrophilic binding. We also found one case, discussed below, where the hydroxyl group of a deoxyribose forms a hydrogen bond close to the site of hydrophobic binding. We now examine the free energy surfaces, as obtained from umbrella sampling and WHAM, which govern the approach of the DNA oligomer to the silica surface. For the ssDNA case depicted in Fig. 5, two bases, guanine and cytosine at the 5′ end, were constrained by a harmonic potential in each sampling window. Because ssDNA is so flexible, the z-component of the centers of mass of bases 3 and 7 counting from the 5′ end were constrained to prevent new attachment forming during this process. The x- and y-components of bases 3 and 7 were free to adjust during the detachment of the guanine and cytosine at the end of the chain to prevent strain developing during the detachment. The change in reaction coordinates and free energy with successive umbrella sampling windows is shown in Fig. 8. Detachment from the silica surface was accomplished in three steps. First, the distance between the surface and guanine center of mass was steadily increased by 0.913nm in sampling windows 1-39 while distance between surface and cytosine was fixed, as traced by the green and red curves in Fig. 8. This breaks most of the guanine-surface interaction without significant distortion of the DNA. There are no associated hydrogen bonds broken during this initial stage of the detachment. At the end of this series of windows, the free energy levels off, as can be seen in the plateau of the purple curve in windows 33-39. After guanine was detached from the surface, the cytosine center of mass was steadily moved by 1.01nm from the surface in the series of sampling windows 40-83 while guanine was fixed. Again, this breaks most of the cytosine-surface interaction without distortion of the DNA. During the latter stages of cytosine detachment from the surface a hydrogen bond involving a deoxyribose hydroxyl group is broken (blue curve in Fig. 8). The rise of the sugar OH-surface distance in Fig. 8 be15




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group of the silica surface. A binding free energy of 8.25kJ mol−1 for a sugar OH group was established in section 4.2 (see Fig. 10).

Figure 11: Hydrogen bonding for deoxyribose sugar of ssDNA.

5 Discussion and Conclusion One of the main conclusions of our work is that phosphate-silanol and hydrophobic interactions are the principal mechanisms for binding of DNA to silica. These short-range attractions can be sufficiently strong to overcome the electrostatic repulsion between negatively charged DNA and a negatively charged silica surface. While DNA and silica above its isoelectric point (∼ pH 3) are both negatively charged, the repulsion between silica and DNA is weak because it is effectively screened by the counter-ions near both surfaces. Both silica and DNA are composed of functional groups that may be either positive or negative, hydrophobic or hydrophilic. Binding is a matter of overcoming charge repulsion by aligning functional groups with complementary properties. Hydrophobic attachments, where a nucleobase lies against a region of the silica surface free from hydrophilic silanols, each contributed from −73 to −190kJ mol−1 . Including cases that were not discussed in section 4.1, each silanol-phosphate interaction, where the oxygen of a phosphate group closely approaches the hydrogen of a surface silanol, can contribute over −65kJ mol−1 to the overall binding energy. Cases where the DNA oligomer formed only one phosphate-silanol interaction were presented in section 4.1. We also encountered

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cases where the oligomer formed more than one phosphate-silanol attachment. Per attachment, we generally found hydrophobic interactions to be the strongest interactions. However, phosphate-silanol binding interactions strongly outnumbered hydrophobic interactions (Table 2), especially for dsDNA. Hydrophobic interactions were so infrequent in our dsDNA simulations because only a terminal base pair unfolded to allow one member of the pair to lie against the surface. Our observation that the hydrogen bonds between terminal base pairs of dsDNA were most labile is in accord with previous simulations. In prior work on the same Drew-Dickerson dsDNA dodecamer, the terminus of the dsDNA was observed to occasionally fray or open,92, 93 or for the gap between base pairs to widen near the terminals.94, 95 Hence phosphate-silanol and hydrophobic interactions were of roughly equal importance for ssDNA, while phosphate silanol interactions are more important for dsDNA. In comparison, auxiliary polar interactions at the periphery of a hydrophobic site, and surface-sugar hydroxyl interactions played a minor role. In other simulation work, hydrophobic interactions between DNA bases and ordered surfaces have been reported. Aksimetiev, Schulten and co-workers reported hydrophobic attachment of DNA bases to crystalline Si3 N4 .49–51 Graphene56 and carbon nanotubes57 were also found to participate in hydrophobic interactions with DNA bases. Another main result is the identification of several factors which explain why ssDNA is attracted to silica more than dsDNA: 1) ssDNA is more flexible, and therefore able to maximize the number of complementary DNA-silica interactions. In a series of runs in which DNA was placed near a neutral DNA surface, ssDNA formed 4 binding sites per run, while dsDNA formed less than 2. The number of each type of interaction – phosphates-silanol, hydrophobic, and sugar hydryoxyl – was less for dsNDA compared to ssDNA. 2) ssDNA has an increased ability for hydrophobic attachment to silica because the bases of ssDNA do not have to unpair with their hydrogen bond partners, as do the bases of dsDNA. 3) The linear charge density of dsDNA is twice that of ssDNA. Our calculated binding free energies are likely underestimates. To explore DNA binding to silica, lengthy molecular dynamics simulations are required, including extensive sampling for free energy calculations. Out of necessity, this work is based on empirical force fields. In addition, after DNA was allowed to bind to silica, we randomly dissociated silanol groups by removing the hydrogens of randomly selected silanol

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groups and changing the oxygen species from hydroxyl oxygen to O− . This procedure sometimes left surface O− underneath the DNA chain. We probably underestimated the binding free energy because in actuality the dissociation of silanols would not be random. Instead, silanol dissociation would react to the DNA placement so as to minimize the overall free energy. Experimental evidence for DNA binding to silica under conditions where the silica surface carries a negative charge has come in various forms, as summarized in the introduction. Typically, some of the factors listed above have been proposed to explain binding in any one work. Yeung and co-workers have proposed that hydrophobic interactions and hydrogen bonding of unpaired bases are the main driving force of adsorption.26 Mao and co-workers studied DNA binding to silica by Fourier-transform infrared spectroscopy.96 The results were explained as the formation of phosphate-silanol hydrogen bonds. Later, Mercier and Savoie studied the interaction of DNA with various types of silica particles by infrared and Raman spectroscopy.20 They disputed the spectroscopic assignments of Mao et al., although they also concluded that the spectrum indicated phosphate-silanol interactions. Kwon and co-workers21 also found that phosphate groups formed strong H-bonds with neutral silanols ( 129kJmol−1 ). Finally, Kwon et al. pulled DNA from a phosphorylated dextran surface in atomic force microscopy experiments. They interpreted their data in terms of phosphatesilanol attachments. We conclude with perhaps a provocative statement. Much has been written about the uniqueness of the water-biomolecule interface.97–100 Silica is a material that is not considered to be an analog to biological molecules. Yet, the silica surface is a disordered patchwork of hydrophilic and hydrophobic regions, much like the surface of a protein. Indeed, the interaction of HIV nucleocapsid protein and DNA has been discussed as a combination of hydrogen bonding and hydrophobic interactions, in terms very similar to our treatment of the DNA-silca interaction.101 Therefore, comparison of water near biological molecules with water near silica may be a useful way to ascertain which properties of water near biological molecules are truly unique.

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Acknowledgements This material is based upon work supported by the National Science Foundation under Grant No. EEC0914790. The calculations reported here were made possible by a grant of resources from the Ohio Supercomputer Center. This information is available free of charge via the Internet at http://pubs.acs.org

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Table 1: Lennard-Jones potential parameters of siloxane (OX ), silanol (OH ), and dissociated silanol (OM ) oxygens that were optimized to best reproduce ab initio data from fragment calculations. The charge parameters are derived from the BKS potential.69 silica atom types charge (e) σ(Å) ǫ(eV) OX (siloxane) −1.2 3.02 4.691 × 10−2 OH (silanol) −1.2 3.06 9.086 × 10−3 OM (dissociated silanol) −1.6 2.95 2.352 × 10−2 Si 2.4 – 0 H (silanol) 0.6 0 0

Table 2: Binding statistics for 8 independent simulations for a ssDNA oligomer, 8 independent simulations for a dsDNA oligomer. All of the dsDNA simulations resulted in binding to an undissociated silica surface, while 7 of the 8 ssDNA runs led to binding.

ssDNA dsDNA

binding events 7 8

phosphate 19 11

binding sites base (hydrophobic) deoxyribose sugar 7 4 1 1

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(a)

(b)

Figure 5: Guanine and a cytosine of ssDNA oligomer bound to hydrophobic regions of silica surface. (a) and (b) are the same picture but DNA is invisible in (b). Larger red surface atoms are dissociated silanols and white dots are hydrogen atoms. In both snapshots, water and counter-ions are not shown.

(a)

(b)

Figure 6: A cytosine of dsDNA is bound to hydrophobic region of silica surface. (a) and (b) are the same picture but DNA is invisible in (b). Large red spheres are dissociated silanols and white dots are hydrogen atoms.

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Figure 11: Hydrogen bonding for deoxyribose sugar of ssDNA.

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DNA Binding to the Silica Surface - ACS Publications - American

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