High-Density Noncovalent Functionalization of DNA by Electrostatic Interactions

Article abstract of DOI:10.1021/jacs.5b05432

Preserving DNA hybridization in organic solvents could someday serve to significantly extend the applicability of DNA-based technologies. Here, we present a method that can be used to solubilize double-stranded DNA at high concentrations in organic media.

Full text of DOI:10.1021/jacs.5b05432

Article
pubs.acs.org/JACS
High-Density Noncovalent Functionalization of DNA by Electrostatic
Interactions
Wei Chen, Jennifer Y. Gerasimov, Pei Zhao, Kai Liu, and Andreas Herrmann*
Zernike Institute for Advanced Materials, Department of Polymer Chemistry, University of Groningen, Nijenborgh 4, 9747 AG
Groningen, Netherlands
S
* Supporting Information
ABSTRACT: Preserving DNA hybridization in organic solvents
could someday serve to significantly extend the applicability of
DNA-based technologies. Here, we present a method that can be
used to solubilize double-stranded DNA at high concentrations in
organic media. This method requires first precipitating a DNA
molecule from the aqueous environment with an anilinium
derivative and subsequently exchanging this moiety with an
amine-containing surfactant in organic solvent. We demonstrate
that this method yields complete exchange of the surfactant and
allows for the modification of DNA with hydrophobic primary,
secondary, and tertiary alkylamines and ordered functional π-
systems. Using this approach, we fabricate a multichromophoric
light harvesting system that would be unattainable by traditional
methods. Additionally, this method makes it possible to use small,
hydrophilic molecules to solubilize DNA in organic solvents, which reduces the shielding around the DNA and makes the
macromolecule more accessible for further chemical modification. We believe that this approach will prove tremendously
beneficial in expanding the scope of DNA-based nano- and biotechnologies.
fundamental investigations, DNA−surfactant complexes have
also been utilized to manipulate the mesophase behavior of
liquid crystals,8b,c,11 to act as an integral element for
electronics,12 to serve as a scaffold for biomineralization,13 to
fabricate organogels,14 and as a vehicle for gene delivery.15
Unfortunately, the broader integration of these materials into
functional systems and devices is limited by the solubility of the
surfactant used. As it stands, the solubilizing surfactant is
constrained to having linear alkyl chains with lengths ranging
from 8 to 16 carbons.8 To enable exchange of the metal
counterion on the DNA backbone with a cationic surfactant,
the lipid moiety needs to be sufficiently hydrophilic to be
introduced into the aqueous phase, but hydrophobic enough to
cause DNA aggregation.8 Very few cationic amphiphiles
currently meet these requirements, which imposes rather rigid
constraints on the innovation of nonaqueous DNA technolo-
gies.12
In this contribution, we present a novel method that
overcomes solubility limitations and allows the electrostatically
driven decoration of DNA with a much wider range of
functionalities. To introduce DNA-complexing molecules that
exhibit poor solubility in water, we developed a two-step
method that relies on a water-soluble surfactant to solubilize
the DNA in the organic phase, where it can subsequently be
INTRODUCTION
■
Aside from its role as the universal carrier of genetic
information, DNA has found widespread application in
directing the bottom-up fabrication of nanoobjects and hybrid
assemblies. Due to its rigid structure and its programmable self-
recognition properties,1 double-helical DNA may be imple-
mented as a structural scaffold, or template, to organize
materials in one, two, and three dimensions.2,3 DNA-mediated
scaffolding thus provides the means to exercise spatial control
over reactions and catalytic processes at the nanometer
scale.2a−c,3b Furthermore, DNA templates integrate seamlessly
into existing DNA technologies, among them, sensors,4
photonic wires,5 and light-harvesting systems.6
While most DNA technologies are developed for use in
aqueous environments, the demonstration that cationic lipids
can solubilize DNA in organic solvents has triggered growing
interest in employing DNA in nonaqueous systems.7
Solubilization in nonpolar organic solvents is possible because
cationic head groups electrostatically interact with phosphate
groups to displace the charged metal cations. Subsequently,
lipophilic tail groups induce cooperative hydrophobic inter-
actions, promoting the aggregation of DNA and the entropi-
cally driven release of salt.8 As a result, the DNA−lipid complex
precipitates out of the aqueous solution, but can be easily
dissolved in many organic solvents. In the organic phase,
DNA−lipid complexes have been used to study mechanical7,9
and conductivity properties of DNA.10 Apart from these
Received: May 26, 2015
© XXXX American Chemical Society
A
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exchanged for a more hydrophobic amine-containing surfactant.
We found, however, that simple substitution of surfactants is
rather problematic due to the infrequent dissociation of ion
pairs in the organic phase. We therefore introduced an
energetically favorable proton transfer to accompany the
surfactant exchange, which drives the reaction to completion.
This strategy is the first reported approach to functionalizing
DNA in the organic phase by ligand exchange. We demonstrate
that this approach is compatible with a broad range of
hydrophobic surfactants, including long chain hydrocarbons
and conjugated π-systems as well as hydrophilic alkylamines
that would not otherwise induce the precipitation of DNA in
aqueous solutions.
RESULTS AND DISCUSSION
■
DNA Precipitation. To solubilize DNA in an organic
solvent, we introduce 4-(hexyloxy)anilinium (ANI) into an
aqueous solution of double-stranded DNA (dsDNA, 2000 base
pairs). As the cationic ANI headgroup electrostatically interacts
with the anionic phosphodiester backbone, a hydrophobic
hydrocarbon shell envelops the dsDNA molecules.16 As a
result, the DNA−ANI complex precipitates out of solution and
is collected by centrifugation.
Figure 1. 1H NMR spectrum of the DNA−DA complex
(DNA−+NH3C12H25), DA (Cl−+NH3C12H25), and dodecylamine
(NH2C12H25) in d-DMSO.
scattering behavior of a long-chain dodecylammonium lipid−
DNA complex in 4:1 CHCl3/MeOH and a short-chain
triethylammonium−DNA complex in MeOH. To avoid
unspecific structure formation, we used a short nonself-
complementary synthetic DNA oligomer (22mer), synthesized
in-house to prepare the above complex. The DNA concen-
tration was found by UV absorption to be 75 μM for the long-
chain complex and 100 μM for the short-chain complex. The
raw correlation data show no correlation between the intensity
autocorrelation function and the lag time, which demonstrates
that neither the DNA−dodecylammonium (Figure S1) nor the
DNA−triethylammonium (Figure S2) complex form aggregates
at high concentrations (75−100 μM). Further, the broadened
NMR signature is only apparent for the proton near the DNA
strand while the proton at the end of the ligand chain (0.8
ppm) does not exhibit this phenomenon. It is therefore
reasonable to deduce the restricted mobility rather than
aggregation causes a decrease in resolution of the triplet from
the amine group; otherwise, every proton signal should exhibit
peak broadening in the NMR spectrum. The signal at 1.15
ppm, assigned to the other methylene groups in DNA−DA,
appears at higher field in relation to uncomplexed DA. This
behavior can be attributed to a difference in the environment
surrounding the alkyl chains when they are complexed to the
DNA in a brush-like structure, where neighboring chains are in
contact with each other, as opposed to the free state, where the
alkyl chains are surrounded by solvent. Additionally, the peaks
at 6.69 ppm, which belong to the benzene ring of ANI, are
absent in the spectrum of the DNA−surfactant complex
(Figure S3). This set of NMR experiments demonstrates that
the ANI moieties were completely replaced by DA.
Unexpectedly, no proton signals originating from the DNA
were detected in the spectrum of the complex, indicating a high
propensity of DA to screen DNA proton resonances.
ANI Substitution with Saturated Aliphatic Surfac-
tants. As a proof of principle experiment, we investigate the
substitution of DNA-complexed ANI with dodecylaminea
surfactant that is insoluble in water and thus a poor candidate
for traditional methods of DNA modification by cationic
surfactants (Scheme 1). The substitution was carried out in a
Scheme 1. Two-Step Process for the Formation of a DNA−
Surfactant Complex with Amine Surfactants
mixture of methanol and chloroform (4:1 CHCl3/MeOH),
using a 3-fold excess of amine-containing surfactant in relation
to the negative charges of the DNA. The final concentration of
DNA is 1 μM, and that of the surfactant is 12 mM. After mixing
and stirring for about 5 min, the solution was transferred into
regenerated cellulose dialysis tubing (molecular weight cutoff,
10.000 Da) and dialyzed against CHCl3/MeOH to remove
excess dodecylamine and ANI.
1
After purification through dialysis, the H NMR spectra of
dodecylammonium (DA) chloride and pristine dodecylamine
were compared to the spectrum of the DNA−DA complex
(Figure 1). The peak of the α-methylene group in the spectrum
of the DNA−surfactant complex (2.72 ppm) appears in a
position similar to the uncomplexed DA (2.76 ppm), but is
shifted downfield by 0.2 ppm in comparison to the free
dodecylamine. We interpret this as evidence that the DNA-
encapsulating surfactant is present in the charged state. In the
spectrum of the protonated DA, the α-methylene peak is well-
resolved as a triplet, whereas the peak appears broad and
unresolved upon interrogation of the DNA−surfactant
complex. The broadening of the signal can be explained by
the restricted mobility of the surfactant when it is localized
around DNA. Alternatively, the broad signal could indicate the
aggregation of the DNA−lipid complex. To exclude the
possibility of aggregation, we examined the dynamic light
Optical methods were used to further characterize the
DNA−DA complex. The ultraviolet−visible (UV/vis) spectrum
of the complex exhibits the distinctive DNA absorbance
maximum at 260 nm, indicating that DNA is indeed dissolved
in CHCl3/MeOH (Figure 2). Circular dichroism (CD)
spectroscopy provides structural information about the
DNA−DA complex in organic media. Positive and negative
CD signals at 289 and 258 nm, respectively, are indicative of
B
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positive and negative ellipticity at 284 and 247 nm, but with
higher CD intensity of both positive and negative peaks due to
the formation of the double-stranded helical structure.
ANI Substitution with Conjugated Polycyclic Surfac-
tant. DNA has proven to be a very promising template to
spatially control the arrangement of photoactive materials on
the nanoscale20 and has been used for the fabrication of
luminescent thin films via precise arrangement of fluorescent
donors and acceptors.21 Here, we synthesize a terthiophene
conjugate with an amine headgroup, designed to form a
supramolecular assembly of functional π-conjugated systems
around a DNA double helix (Figure 3a). The synthesis and
Figure 2. UV−vis and CD (inset) spectra of the DNA−DA complex.
DNA concentration is 0.02 μM in 4:1 CHCl3/MeOH.
the right-handed double helix structure of DNA (Figure 2,
inset). As previously observed upon complexation with cationic
surfactants, CD peaks shift to longer wavelengths and decrease
in intensity compared to double stranded DNA in aqueous
solvent. This has previously been attributed to a transition from
the B-form of DNA, found under physiological conditions, to
the C-form.17a More recent studies, however, have concluded
that the changes in the CD signal are a result of minor changes
in the interactions between the bases and that the double helix
maintains the B-form.17b,c The transition could be the result of
the absence of water molecules around DNA that interact with
the oxygen of ribose, phosphate, and minor or major
grooves.7a,17
Finally, the successful exchange of the cationic surfactant was
verified by Fourier Transform Infrared (FTIR) spectroscopy. It
can be seen from the IR spectrum (Figure S2) that the DNA−
DA complex shows characteristic ammonium bands that absorb
in a range between 3191 and 3142 cm−1 and at 1650 cm−1,
+
corresponding to N−H stretching and asymmetrical −NH3
deformation vibrations, respectively.18 The IR-bands at 1058
and 1238 cm−1 are assigned to symmetric and asymmetric
stretching vibrations of PO2− groups of DNA.19
Other alkyl amines that cannot be attached to DNA in a
direct, single-step procedure, including octadecylamine, dio-
ctadecylamine, and trioctylamine, were also shown to be
compatible with this two-step method of ligand exchange. For
characterization, please see Supporting Information (Figures
S5−S10). This approach also works well with a longer synthetic
duplex. We chose two complementary nucleotides (48mer),
oligo 1 and oligo 2, used in DNA origami, to demonstrate the
feasibility. The sequences can be found in the Supporting
Information. Both the hybridized duplex and single-stranded
oligonucleotides (oligo 1 and 2) were first precipitated by ANI
in the aqueous phase and subsequently extracted into a mixture
of methanol and chloroform (4:1 CHCl3/MeOH), where ANI
was substituted by dodecylamine. The final concentrations of
the duplex and single-stranded oligomers were adjusted to 1.2
μM by monitoring the UV absorption at 260 nm. CD data
(Figure S11) of oligo 1 in the DNA region exhibit a broad
positive ellipticity peak with a maximum at 270 nm. The
maximum negative ellipticity is difficult to identify due to the
high noise from organic solvent below 245 nm. Oligo 2 shows
both positive and negative ellipticity at 284 and 255 nm,
respectively. The duplex shows a similar profile to Oligo2, with
Figure 3. Molecular structure of terthiophene modified with an amine
group for complexation with DNA (a). UV/vis absorption spectra of
films of terthiophene and the DNA−terthiophene complex prepared
from 0.5 μM DNA complex solution (b). Inset: CD spectrum of the
DNA−terthiophene complex.
characterization of this compound are detailed in the
Supporting Information. Terthiophene is soluble in most
organic solvents and can therefore be introduced to encapsulate
DNA according to the procedure described above. After
thorough purification of the DNA−terthiophene complex in
the organic phase (4:1 CHCl3/MeOH), which resulted in a
solution containing 0.5 μM DNA complex, thin films were cast
and examined by UV/vis and CD spectroscopy.
The UV/vis absorption spectra of pristine terthiophene and
the DNA−terthiophene complex differ markedly from each
other. In the spectrum of DNA−terthiophene a much larger
absorption peak is detected at a wavelength of 260 nm in
relation to the pristine terthiophene moiety, which can be
attributed to the presence of the nucleic acid component. The
C
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maximum absorption of terthiophene is located at 356 nm
while the corresponding maximum of the DNA−terthiophene
complex is found at 374 nm, exhibiting an 18 nm bathochromic
shift. This spectral behavior is indicative of the formation of J-
aggregates of the aromatic oligothiophene system.4e
CD data in the spectral region of terthiophene absorption
exhibit positive ellipticity with a peak maximum at 415 nm and
weak negative ellipticity at 369 nm, with zero-crossing at 378
nm (Figure 3b, inset). In contrast, for bare terthiophene films,
no CD signal is measured. The CD data suggest that the
terthiophene molecules are assembled in a right-handed helix as
a result of being complexed with the DNA molecule.22 These
experiments demonstrate that through the application of our
new surfactant exchange strategy, it is possible to organize
functional molecules in a way that enables the production of
supramolecular π-system architectures that employ DNA as a
template. Due to the hydrophobic character of extended
aromatic units, such chromophore ensembles are not attainable
via existing methods for formation of DNA−surfactant
complexes.
ANI Substitution with Pyrene To Mimic Light Harvest-
ing Systems. Having demonstrated ligand exchange with an
aromatic surfactant, we further explore this strategy to construct
a noncovalent light harvesting system (LHS). Such complexes
play a key role in photosynthesis by funneling electronic
excitations, which are induced by sunlight, toward the reaction
center by energy transfer.23 Due to the importance of this
process, several model LHSs have been synthesized.24 To
fabricate a DNA−surfactant complex that mimics an LHS, a
22mer oligonucleotide was labeled at one terminus with a
chromophore that exhibits a large Stokes shift (490LS, ATTO-
TEC). This chromophore is characterized by an optical
absorption ranging from 450 to 550 nm (absorption maximum
496 nm) and an emission maximum at 620 nm. Using the novel
surfactant exchange method described in the previous sections,
the 490LS-labeled oligonucleotide is complexed with a pyrene-
modified surfactant (Figure 4a). The synthesis and character-
ization of this compound are detailed in the Supporting
Information. The UV/vis absorption of DNA−490LS pyrene
complex (black curve) is shown in Figure 4b, which exhibits the
characteristic maximum absorption of pyrene (250 to 280, and
300 to 355 nm) and that of DNA (260 nm). The weak
absorption peak at 496 nm can be assigned to 490LS. As a
control, we examine the emission spectrum of a DNA−pyrene
surfactant complex that is not labeled with 490LS. Both DNA−
490LS−pyrene (red curve) and DNA−pyrene (blue curve)
exhibit a broad emission peak between 420 and 500 nm, with a
maximum at 450 nm (Figure 4b). These bands are ascribed to
excimer fluorescence that is caused by the aggregation of
pyrene along the DNA scaffold.25 Due to the overlap of pyrene
emission and 490LS absorption, in addition to the close
proximity of both types of chromophores within the DNA−
surfactant complex, energy transfer is observed as 490LS
emission at 610 nm. Comparing the LHS with the control, the
spectrum of the DNA−490LS−pyrene complex exhibits lower
pyrene photoluminescence in relation to the DNA−pyrene
complex, indicating that the energy is transferred to the
acceptor. In a separate experiment, we determined that when
pyrene is introduced, but not complexed with 490LS-labeled
DNA, no energy transfer is observed. These photophysical
measurements prove that a simple surfactant exchange method
can enable the successful construction of a functioning LHS.
Figure 4. (a) Illustration of energy transfer from DNA bonded pyrene
to 490LS in the LHS. (b) UV/vis absorption (black) and emission
(red) of DNA−490LS−pyrene compelx. The emission of a DNA−
pyrene complex in organic solvent (4:1 CHCl3/MeOH) with
concentration 0.4 μM, absent 490LS is presented as a control
(blue). The excitation wavelength for all emission spectra is 350 nm.
ANI Substitution with Water-Soluble Surfactants.
Reducing the steric hindrance of the surfactant shell around
the DNA could potentially have a significant impact on the
effectiveness of noncovalent DNA functionalization26 and
DNA-mediated catalysis in the organic phase.27 DNA
solubilization by small ligands in organic solvents presents a
different set of challenges. Small amine ligands are more
hydrophilic compared to larger surfactant molecules and thus
do not evoke DNA precipitation in aqueous environments,
making the complex more difficult to isolate.28 Since the two-
step exchange protocol does not rely on coprecipitation of
DNA with the selected surfactant in an aqueous solvent, we can
investigate the lower size limits of small ligands that keep DNA
soluble in the organic phase. While amines with a lower
molecular weight, such as diethylammonium and dimethyl-
ammonium, precipitate in most organic solvents, we found that
triethylammonium can be used to replace ANI in the organic
phase and solubilize DNA from salmon testes (2000 bp) in
CHCl3/MeOH (for characterization, see Supporting Informa-
tion Figures S12 and S13). Because significantly smaller
cationic ligands are used here than in the previous sections,
the proton signals from the nucleobase and the pentose are
clearly visible in the NMR spectrum of the DNA−
triethylammonium complex (Figure S9). The peaks at 4.74
ppm (H3′), 4.14 ppm (H4′), 3.88 ppm (H5′, H5″), and 1.78
ppm (H2′) are attributed to protons on the pentose. By
integrating the 1H NMR signals, we determine that the
molecular ratio of pentose to triethylammonium is close to 1:1.
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This is yet another strong indicator that one phosphate group is
complexed with one cationic ligand and that the ligand
exchange proceeds to completion. Although short, unmodified
DNA strands (10−30 bp) have previously been introduced into
tetrahydrofuran and acetonitrile for DNA-templated reactions,
their concentration has been limited to the nanomolar range.26
In contrast, here, micromolar DNA concentrations were
reached in organic solvents with the small counterion
triethylammonium.
Exchange Mechanism. According to models developed to
describe ion-exchange chromatographic separations, the rate of
ion exchange depends on the charge of a given ion and its
mobility in the selected solvent.29 Both of these parameters
determine the degree of ion pair dissociation and are controlled
by electrostatic interactions. According to Coulomb’s law,30 the
force between counterions is inversely proportional to the
dielectric constant of the solvent. To achieve effective
substitution of an ion pair, the exchange process should be
carried out in a solvent with a high dielectric constant (εγ),
such as water (εγ ≈ 80.1), or water mixtures containing polar
solvents, such as acetonitrile (εγ ≈ 37.5). In contrast, we
achieved ligand exchange in a nonpolar environment containing
chloroform (εγ ≈ 4.8), where cation mobility is significantly
lower. The effective, high-yield exchange of the surfactant in a
nonpolar solvent suggests that a chemical process contributes
to the exchange in addition to the purely physical diffusion
mechanism.
We propose the following mechanism to accommodate our
observations. The DNA−ANI interaction can be characterized
as an ionic hydrogen bond between the phosphate of the DNA
backbone and the ammonium group of the ANI. As such, both
electrostatic and acid−base interactions contribute to the
stability of the bond.31 With the introduction of a primary
amine, the acid−base interaction is disrupted because aniline
has a much lower Kb value (∼10−10 M) than the primary amine
(∼10−4 M). Therefore, amines exhibit a much higher reactivity
with phosphoric acid than the aniline group. We postulate that
the substitution of the ANI for the primary amine is the result
of a proton transfer between the two surfactants participating in
the exchange (Scheme 2). This transfer is facilitated by the
phosphate anion, which is transiently protonated and can
therefore react with the amine group of the more basic
surfactant. After the transfer, the phosphate anion electrostati-
cally interacts with the cationic ammonium group. This leaves
the now-neutral aniline free to dissociate from the DNA−
ammonium complex. In accordance with our theory, the rate of
substitution is determined by the differences in Kb values
between the primary amine and aniline. Since the basicity of
primary, secondary, and tertiary amines is orders of magnitude
larger than that of aniline, there is sufficient driving force to
ensure complete cation exchange, as observed in our experi-
ments.
CONCLUSION
■
We have developed a robust and generic protocol for the
noncovalent modification of single-stranded and double-
stranded DNA by ligand exchange in organic solvents. The
method requires first precipitating a DNA molecule with an
anilinium compound from the aqueous environment and
subsequently exchanging this moiety with an amine in an
organic solvent. This strategy provides an alternative way to
fabricate DNA−lipid complexes, overcoming the very restricted
window of surfactant solubility required for the direct exchange
mechanism. Due to the large driving force of proton exchange
between the anilinium and the amine, the exchange process
runs to completion, as proven by NMR studies.
Therefore, the DNA−surfactant systems reported herein
differ significantly from the ones reported earlier,7−16 where the
choice of surfactants was limited to a great extent. Moreover,
the electrostatic complexes depart from previous work where
the complexation of the DNA with the surfactant enabled
overcoming solubility incompatibilities to modify hydrophilic
nucleic acid moieties with hydrophobic units through covalent
bond formation.8d This novel noncovalent method of
functionalization allows the fabrication of DNA ensembles in
the organic phase where the double helix is surrounded by
primary, secondary, and tertiary hydrophobic alkylamines,
ordered functional π-systems, and even small hydrophilic
molecules. Finally, we demonstrate the successful construction
of a multichromophoric light harvesting system based on
DNA−surfactant complexes. We believe that this approach may
greatly accelerate the fabrication of functional DNA nanostruc-
tures.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b05432.
■
S
Detailed description of the methods, materials, synthesis
of ANI, synthesis of N,N-diethyl-3-((5″-hexyl-[2,2′:5′,2″-
terthiophen]-5-yl)oxy)propan-1-amine, synthesis of pyr-
ene, 1H NMR of DNA−ANI complex, Fourier transform
infrared spectra of DNA−lipid complexes, character-
ization of DNA−octadecylammonium, −dioctadecyl-
ammonium, −trioctylammonium, and −triethyl-
ammonium complexes (PDF)
Scheme 2. Schematic Representation of the Mechanism of
Exchanging the ANI Component with a Primary Amine
AUTHOR INFORMATION
Corresponding Author
*a.herrmann@rug.nl
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
W.C. and A.H. were supported by the EU (ERC starting grant
and STREP project Micreagents), The Netherlands Organ-
ization for Scientific Research (NWO-Vici), and the Zernike
E
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DOI: 10.1021/jacs.5b05432
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX