PH-switchable helicity of DNA-templated assemblies

Article abstract of DOI:10.1002/anie.200903507

Coming together: Oligothymine is used as a template to self-assemble complementary nonchiral naphthalene guests. Depending on the protonated state of the guest, left- or right-handed DNA-templated self-assemblies are formed (see picture). The templated as

Full text of DOI:10.1002/anie.200903507

Angewandte
Chemie
DOI: 10.1002/anie.200903507
Host–Guest Systems
pH-Switchable Helicity of DNA-Templated Assemblies**
Pim G. A. Janssen, Amparo Ruiz-Carretero, David Gonzꢀlez-Rodrꢁguez, E. W. Meijer, and
Albertus P. H. J. Schenning*
DNA is among one of the most promising building blocks to
construct functional nanostructures with geometrical, size,
and positional control.[1–3] This biomolecule has been used as a
template for the self-assembly of nanoparticles,[4] chromo-
phores,[5–7] and lipids,[6] while predefined complex nanosized
structures have been created by sticky-end cohesion.[8]
Previously, we reported on the templated self-assembly of
diaminotriazine-equipped naphthalene and oligo(p-phenyl-
enevinylene) guest derivatives selectively binding to an
oligothymine template (Tn, where n is the number of thymine
units) by hydrogen bonding.[6] In these constructs the chiral
single-stranded (ss) DNA host templates a supramolecular
strand of achiral chromophores, yielding a right-handed
organization of the dye guests (Scheme 1). The efficiency of
this templated self-assembly depends on the host–guest and
guest–guest interactions and can be described by a templated
assembly model based on a one-dimensional Ising model.[6a]
To enhance this efficiency, we have now synthesized an
achiral naphthalene guest derivative (P) equipped with a
diaminopurine[9] hydrogen-bonding unit, having a larger p
surface than diaminotriazine, that binds to the oligothymine
Tn template (Scheme 1). Unexpectedly, the helicity of this
DNA-templated assembly can be switched by changing the
pH value as a result of protonation of the guest (Scheme 1).
Helix reversals have been observed for double-stranded (ds)
DNA in which cation binding to the phosphate backbone
causes a transition from right-handed B-DNA to left-handed
Z-DNA.[10,11] Stereomutation has also been reported in
synthetic and supramolecular helical polymers, in which the
helicity is controlled by temperature, pH value, solvent, light,
Scheme 1. The molecular structures of the host template Tn and the
guest (P) and schematic representation of pH-switchable helicity of
the ssDNA-templated self-assembly. (T=temperature and C=concen-
[*] P. G. A. Janssen, A. Ruiz-Carretero, Dr. D. Gonzꢀlez-Rodrꢁguez,
tration).
Prof. Dr. E. W. Meijer, Dr. A. P. H. J. Schenning
Laboratory of Macromolecular and Organic Chemistry
Institute for Complex Molecular Systems
Eindhoven University of Technology
P.O. Box 513, 5600 MB Eindhoven (The Netherlands)
Fax: (+31)40-245-1036
or chiral stimuli.[12] Switching the helicity of DNA-templated
assemblies, however, has not been reported to date.[13]
The diaminopurine naphthalene guest molecule (P) was
synthesized by a convergent route and fully characterized.[14]
Temperature- and concentration-dependent UV/Vis meas-
urements show that P is molecularly dissolved in 100 mm
phosphate buffer at pH 7 until a concentration of at least
1 mm. The absorption spectrum shows maxima at lmax = 221
and 345 nm, with a vibronic shoulder at 370 nm (Figure 1a).
When P is mixed with T40 in an 80:1 ratio,[15] a slight blue shift
and hypochromicity of the absorption band is observed
(Figure 1a). Simultaneously, a positive Cotton effect in the
E-mail: a.p.h.j.schenning@tue.nl
Homepage: http://www.chem.tue.nl/smo
[**] We acknowledge X. Lou for the MALDI-TOF spectra, M. van Gen-
deren, M. Surin, P. van der Schoot, S. Jabbari-Farouji, and G.
van der Marel for the scientific discussion, K. Pieterse for the
artwork, and the EURYI scheme for the financial support. The
research of D.G.R. was supported by a Marie Curie Intra-European
Fellowship. The research of A.R.C. was supported by a MEC-FPU
Spanish predoctoral grant.
Supporting information for this article, including full experimental
details (general methods, materials, synthetic route and character-
ization of P, sample preparation, and additional figures), is available
on the WWW under http://dx.doi.org/10.1002/anie.200903507.
naphthalene absorption region with the zero-crossing at lz-c
=
338 nm is detected (Figure 1b), thus revealing that the P
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These results show that optimizing the templated self-
assembly is a delicate process in which the guest–guest and
host–guest interactions need to be balanced.
Remarkably, when the pH value of a T40–P (1:80 molar
ratio) solution at 268 K is changed from 9 to 2 the Cotton
effect is reversed, revealing that a left-handed hybrid DNA
complex has been formed at low pH values.[18,19] The zero-
crossing of the Cotton effect (lz-c) is blue-shifted from 338 to
333 nm, and the UV absorption maximum (lmax) shifts from
342 to 337 nm (Figure 2). The change in the UV/Vis spectrum
and the sign change in the Cotton effect take place at the same
pH value (pH ꢀ 5, Figure 3a).[14]
To shed some light on this pH-induced helix reversal, the
pKa of P was determined by monitoring the UV/Vis
absorption as a function of the pH value.[20] The lmax of P at
221 nm at pH 9 (Figure 3a) shifts to 213 nm for P + H+ at
pH 2. The found pKa of approximately 4.8 is in agreement
with the values found in literature for related diaminopurine
derivatives (see below).[21,22] For the absorption maximum at
lmax = 345 nm a similar but less pronounced pH-dependent
transition is observed.[14]
Figure 1. a) Normalized UV/Vis spectra of P and T40–P complex at
pH 7. [P]=0.25 mm and [P]=2[T]T40 =0.5 mm at 268 K, respectively.
b) CD spectrum of T40–P at 268 K and pH 7. c) CD intensity at
l=354 nm upon titration of P to T40 at pH 7 at different temper-
atures. [T]T40 =0.25 mm. d) CD cooling curve at l=354 nm of a T40–P
mixture at pH 7 and fit to the templated self-assembly model.[6a]
[P]=2[T]T40 =0.5 mm.
guests are arranged in a right-handed helix.[6a] As other homo-
ssDNA strands (dA40, dC20; d = deoxy) using similar con-
ditions are not able to induce a Cotton effect in the
naphthalene absorption region (data not shown),[16] it is
concluded that P binds to T40 through Watson–Crick type
H-bonding similar to the previously studied diaminotriazine
derivatives.[6] A Hoogsteen type pair instead of a Watson–
Crick type pair is unlikely, as both possible Hoogsteen
arrangements are sterically hindered.[17] A CD titration
experiment in which P is added to T40 at 268 K (Figure 1c)
shows an inflection point at one equivalent of [P]/[T] (where
[T] is the thymine concentration), thus indicating that P binds
to T40 in a 40:1 ratio. At higher temperatures, the degree of
binding is lower (Figure 1c).
The fraction of occupied template binding sites q for the
T40–P mixture ([P] = 2[T]T40 = 0.5 mm) was determined by
monitoring the CD spectroscopic changes as function of
temperature (Figure 1d). The temperature at which the
templated self-assembly starts is defined as Tte (Figure 4d,
see below).[6] By fitting the temperature-dependent CD data
to the templated self-assembly model (Figure 1d),[6a] a guest–
guest interaction energy e ꢀ À6.4kTp (= À15.2 kJmolÀ1 at
Tp = 285 K) is found. When fitting the titration of P with T40
to the templated self-assembly model, a host–guest interac-
tion g ꢀ À7.5kT (= À17.3 kJmolÀ1 at T= 278 K) is calculated.
For the previously studied diaminotriazine naphthalene
derivative binding to T40, the values are g ꢀ À9kT and e ꢀ
À5.3kTp.[6a] Compared to this system, P has a higher e and
hence, a longer correlation length.[6a] This situation is possibly
due to the larger p-conjugated surface of the diaminopurine
compared to the diaminotriazine H-bonding unit. In contrast,
the host–guest interaction (g) is weaker, explaining the poorer
overall stability compared to the reported templated self-
assemblies of the diaminotriazine naphthalene derivative.[6a]
Figure 2. a) UV/Vis and b) CD spectra of [P]=2[T]T40 =0.5 mm at
268 K for pH values ranging from 9 to 2.[20]
Figure 3. a) CD intensity at 354 nm of [P]=2[T]T40 =0.5 mm at 268 K
and lmax of [P]=0.25 mm as a function of the pH value. b) Part of the
molecular structure of P+H+ in which the oxygen atoms of the
ethylene glycol unit on N-9 stabilize protonation at N-3.
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Based on the data above, the helix reversal occurs at the
same pH range as the protonation of P (Figure 3a), thus
indicating that these processes are related and that the helical
switch in our templated self-assembly is caused by protona-
tion of the guest. It is known that in polythymine at pH 3, the
thymine units are not protonated and the phosphates are
deprotonated.[10] Binding of P + H+ to the phosphate back-
bone is also unlikely, since this process is selective for
oligothymine and no binding is observed for the other homo-
ssDNA strands.[16] Therefore, it seems that the protonated
state of P controls the helicity of the T40–P complex while
preserving the H-bonding pairing.[16] The order of basicity of
the nitrogen atoms in 2,6-diaminopurine is: N-1 ꢀ N-3 >
N-7.[21] N-1 being occupied in H-bonding to the thymines,
protonation is most likely to occur at N-3.[23] Further evidence
was taken from the lower pKa value determined for P (pKa
ꢀ 4.8), when compared to other 2,6-diaminopurine deriva-
tives (pKa ꢀ 5.1),[23] which can be explained by stabilization of
P + H+ through H-bonding with the ethylene glycol unit at
the N-9 position,[24] as shown in Figure 3b. Interestingly,
related N-9-glycol-substituted 2,6-diaminopurine derivatives
also show a small decrease in pKa value (pKa ꢀ 4.9).[21,22]
In short, it seems that N-3 protonation of the guest
molecules results in a thermodynamically different situation
that induces a rearrangement of the T40–P complex with an
inversion of chirality. At low pH values, other forces come
into play that may cause the stabilization of a left-handed
structure. In particular, attractive electrostatic interactions
between the positively charged P + H+ species and the DNA
phosphate backbone may reinforce binding strength (see
Figure S5 in the Supporting Information) and reduce the
electrostatic repulsion between the phosphates in T40. In Z-
DNA, for example, both the increase in distance between the
stacked bases and the decreased angle of rotation between
two base pairs are a result of alternating syn- and anti-
conformations of the glycosidic bonds, caused by less electro-
static repulsion between the phosphates compared to B-
DNA, where all glycosidic bonds have an anti-conforma-
tion.[10] The lower Cotton effect at pH 3 can indicate a
stretched and/or narrower, denser structure, originating from
an increased distance and/or a decreased angle between the
bound guests.[25]
Figure 4. a) CD intensity at l=354 nm upon titration of P to T40 for
pH 3 at different temperatures. [T]T40 =0.25 mm. b) Fits of the titration
at 278 K at pH 3 and 7 to the templated self-assembly model.[6a] c) CD
cooling curve at l=354 nm of a T40–P mixture at pH 3 and 7 and fit
to the templated assembly model.[6a] d) Tet (reciprocal scale) as a
function of [P] (logarithmic scale) obtained from cooling curves of
T40–P mixtures ([P]=2[T]T40) at l=354 nm for concentrations between
0.06 and 1 mm at pH 7 and 3.
tion measurements at pH 3 (Figure 4b), a guest–guest inter-
action energy e ꢀ À6.5kTp (= À16.8 kJmolÀ1 at Tp = 310 K)
and a host–guest interaction g ꢀ À9.3kT (= À21.5 kJmolÀ1 at
278 K) were determined. The guest–guest interaction is
similar to the value at pH 7 (see above) while the host–
guest is more negative. This result implies an improved
stability at pH 3, arising from an additional host–guest
interaction, and supports the presence of secondary attractive
electrostatic interactions in the T40–P + H+ complex.
In conclusion, we have demonstrated that 2,6-diamino-
purine guest molecules can bind to oligothymine strands to
construct assemblies with a pH-switchable stability and
supramolecular helicity. Our studies open unique possibilities
to arrange functional molecules equipped with this hydrogen-
bonding unit into DNA-templated switchable functional
nanostructures.
The templated assembly processes at pH 3 was analyzed
in more detail by monitoring the CD spectroscopic changes as
a function of the temperature. Compared to the results found
at pH 7 (Figure 1), a titration at pH 3 of P to T40 shows a
sharper inflection at one equivalent of guests (Figure 4b). At
higher temperatures the degree of binding is, as expected,
lower (Figure 4a), but the inflection point is clearly main-
tained close to one equivalent, even at 328 K. In addition,
although the shape of the melting curve at pH 3 is similar to
the one obtained at pH 7, the complex at pH 3 exhibits an
increase of Tte, the temperature at which the templated self-
assembly starts, of about 30 K (Figure 4c,d).[6,14] Interestingly,
the variation of Tte as a function of the pH value shows again
the same transition as the protonation of P.[14]
Received: June 29, 2009
Published online: September 15, 2009
Keywords: chirality · helical structures · host–guest systems ·
.
self-assembly · supramolecular chemistry
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[16] A control experiment, in which the complementary single strand
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