Binaphthyl-DNA: Stacking and fluorescence of a nonplanar aromatic base surrogate in DNA

Article abstract of DOI:10.1002/anie.200903194

A flexible hinge allows multiple binaphthyl-modified bases to stabilize DNA duplexes through both intrahelical and extrahelical stacking interactions. Two successive binaphthyl pairs stabilize the duplex structure as efficiently as two successive AT pairs

Full text of DOI:10.1002/anie.200903194

Communications
DOI: 10.1002/anie.200903194
DNA Structures
Binaphthyl-DNA: Stacking and Fluorescence of a Nonplanar Aromatic
Base Surrogate in DNA**
Sven Hainke and Oliver Seitz*
The replacement of canonical nucleobases with artificial
aromatic surrogates allows the incorporation of new functions
into the base stack of DNA. Arenes and heteroarenes have
been introduced as shape mimics of natural bases and as
artificial base pairs to help understand DNA–DNA and
DNA–protein interactions.[1] Many base surrogates exhibit
interesting fluorescence properties, which depend on stacking
interactions with the environment.[1d] This has allowed the
design of probes that report on the structure and function of
enzymes and nucleic acids.[2] Recently, it has been recognized
that oligomeric assemblies of fluorescent base surrogates
offer the interesting opportunity to tune the optical properties
through hybridization-controlled dye–dye interactions.[3]
Typical base surrogates are planar in order to facilitate p-
stacking and hydrophobic interactions within the helical
arrangement of DNA bases. For example, the stacking of
Figure 1. Biphenyl-DNA (Bp), binaphthyl-DNA (Bn), and binaphthyl-
modified oligonucleotides studied in this investigation. Note that the
pyrenes, perylenes, and phenanthrenes has been investigated
in detail.[3a,i,j,4] The design paradigm has also been applied for
the incorporation of planar polycyclic heterocycles such as
cyanine and phenanthridinium dyes.[5,6]
binaphthyl nucleoside exists in two interconverting diastereomeric
forms.
binaphthyl chromophore as a new type of torsionally flexible
dye in DNA.
To the best of our knowledge, the stacking of nonplanar
units in DNA has not been described. We and Leumann et al.
have explored the biphenyl “base” (Bp in Figure 1) as an
intrinsically nonplanar polycycle.[2c,7] However, the stacking
energy gained upon hybridization is sufficient to overcome
the small barrier to rotation (DG ꢀ 10 kJmolÀ1) resulting in
the planarization of the biphenyl residue in the helical base
stack.[8] Interestingly, multiply inserted biphenyl–biphenyl
pairs have been found to stabilize DNA duplexes as a result of
the zipperlike interstrand arrangement of biphenyl base
pairs.[9] We herein demonstrate, perhaps surprisingly, that
stabilization of the duplex structure can also be achieved
when nonplanar base surrogates are stacked.
We studied the 1,1’-binaphthyl ring system, which com-
prises two naphthyl rings that on average are nearly
orthogonal.[10] The rotation about the central bond is slow at
293 K in solution owing to the large barrier to rotation (DG
ꢀ 100 kJmolÀ1).[11] The optical properties of the 1,1’-
binaphthyl chromophore depend upon the viscosity of the
solvent.[10b] For this reason, one may envision using the 1,1’-
The 4-linked 1,1’-binaphthyl C-nucleoside was prepared
by our recently published cuprate-glycosylation method.[12]
The binaphthyl nucleoside was incorporated into oligonu-
cleotides 1Bn–4Bn, 5Bnn, and 5’Bnm. In the first group of
oligonucleotides, 1Bn–4Bn, only one binaphthyl base is
incorporated in different nucleobase environments. The
oligonucleotides 5Bnn are complementary to 5’Bnm, and the
resulting duplexes contain various numbers of successive
binaphthyl units. Several HPLC profiles showed two peaks
(Figure S1 in the Supporting Information). Nevertheless, the
HPLC analysis of a quantitative phosphodiesterase digest
revealed only the five nucleoside components (Figure S2C,D
in the Supporting Information). We assumed that the low
rotation barrier of the naphthyl–naphthyl linkage causes the
formation of diastereomeric mixtures in DNA. The mixture
was fractionated by HPLC methods. However, HPLC anal-
ysis of each fraction showed, again, two peaks. This suggests
that the rotation about the naphthyl–naphthyl linkage is not
sufficiently hindered to prevent epimerization during isola-
tion. This behavior is known from binaphthyl derivatives that
lack substituents at the 2- and 2’-positions.[10b]
We examined the thermal stability of binaphthyl-contain-
ing oligonucleotide complexes by UV melting analysis
(Table 1). The melting curves showed a single transition
indicative of cooperative base pairing (Figure S3 in the
Supporting Information). The replacement of the thymine
base in the TA base pairs in 1T·1’A, 2T·2’A, 3T·3’A, and
4T·4’A by one binaphthyl base in duplexes 1Bn·1’A,
2Bn·2’A, 3Bn·3’A, and 4BnT·4’A, respectively, led to
[*] S. Hainke, Prof. Dr. O. Seitz
Institut fꢀr Chemie der Humboldt-Universitꢁt zu Berlin
Brook-Taylor-Strasse 2, 12489 Berlin (Germany)
Fax: (+49)30-2093-7266
E-mail: oliver.seitz@chemie.hu-berlin.de
[**] This work was supported by Sigma-Proligo.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903194.
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Table 1: Thermal stability of binaphthyl-modified and unmodified
duplexes.[a]
Duplex
X
Y
TM [8C]
5’-TAGTTCTXTGAGAAGGTG-3’
3’-ATCAAGAYACTCTTCCAC-5’
1Bn·1’A
1T·1’A
Bn
T
/
/
45.8
54.6
5’-TAGTTCAXAGAGAAGGTG-3’
3’-ATCAAGTYTCTCTTCCAC-5’
2Bn·2’A
2T·2’A
Bn
T
/
/
47.0
54.8
5’-TAGTTCCXCGAGAAGGTG-3’
3’-ATCAAGGYGCTCTTCCAC-5’
3Bn·3’A
3T·3’A
Bn
T
/
/
51.2
59.9
5’-TAGTTCGXGGAGAAGGTG-3’
3’-ATCAAGCYCCTCTTCCAC-5’
4Bn·4’A
4T·4’A
Bn
T
/
/
54.6
60.4
Figure 2. Space-filling representations of possible structures of oligo-
nucleotide duplexes containing a) one binaphthyl residue (Bn) (in the
S form, syn to deoxyribose) and b) two adjacent binaphthyl residues
(upper Bn in the S form and syn, lower Bn in the R form and anti to
deoxyribose). The sugar phosphate backbone is shown in gray, the
nucleobases in blue, and binaphthyl in red. See the Supporting
Information for details.
5’-CGGCACGAGCGGC-3’
3’-GCCGTGCTCGCCG-5’
5·5’
/
/
64.8
5Bn·5’
5T·5’
5A·5’
Bn
T
A
/
/
/
58.7
55.5
57.8
5’-CGGCAXCGAGCGGC-3’
3’-GCCGT-GCTCGCCG-5’
5Bn·5’Bn
5T·5’T
5A·5’A
5T·5’A
Bn
T
A
Bn
T
A
59.6
56.5
57.9
66.4
5’-CGGCAXCGAGCGGC-3’
3’-GCCGTYGCTCGCCG-5’
less stable than the unmodified duplex 5·5’. The introduction
of the additional binaphthyl unit in 5Bn·5’Bn conferred no
further destabilization. Remarkably, the stability of the
duplexes progressively increased as the number of successive
binaphthyl residues increased. For example, the additional
binaphthyl pair in the duplex 5Bn2·5’Bn2 provided an increase
of duplex stability from TM = 59.68C for the 5Bn·5’Bn duplex
to TM = 67.48C for the 5Bn2·5’Bn2 duplex. To our surprise,
duplex 5Bn3·5’Bn2, which contains five successive binaphthyl
bases, was even 5.28C more stable than unmodified duplex
5·5’.
T
A
5Bn2·5’Bn
5T2·5’T
5A2·5’A
5T2·5’A
Bn
T
A
Bn
T
A
62.7
53.0
53.2
58.8
5’-CGGCAXXCGAGCGGC-3’
3’-GCCGT Y GCTCGCCG-5’
T
A
5Bn·5’Bn2
5T·5’T2
5A·5’A2
5T·5’A2
Bn
T
A
Bn
T
A
62.8
52.5
51.6
58.7
5’-CGGCA X CGAGCGGC-3’
3’-GCCGTYYGCTCGCCG-5’
T
A
The pronounced decrease of duplex stability upon intro-
duction of one binaphthyl pair and the significant stabilization
of duplexes that contain two or more consecutive binaphthyl
units is noteworthy. This behavior was not observed with the
natural nucleobases thymine and adenine. The thymine–
thymine (5T·5’T) and adenine–adenine pairs (5A·5’A) were
less stabilizing than the corresponding binaphthyl–binaphthyl
pair in 5Bn·5’Bn. Each additional thymine or adenine residue
in duplexes 5Tn·5’Tm and 5An·5’Am (n ꢁ 1, m ꢁ 1) resulted in
further destabilization. This is in stark contrast to the
binaphthyl series, where each additional binaphthyl residue
stabilized the duplex (Figure 3). Duplexes 5Bn3·5’Bn2, which
contain five successive binaphthyl bases, are 208C more stable
than the thymine- and adenine-containing duplexes 5T3·5’T2
and 5A3·5’A2. Interestingly, while one binaphthyl–binaphthyl
pair (5Bn·5’Bn) was 6.88C less stable than an AT pair
(5T·5’A), two succeeding binaphthyl pairs (5Bn2·5’Bn2) were
1.48C more stable than two succeeding AT pairs (5T2·5’A2).
This suggests that two adjacent binaphthyl pairs stabilize
duplex architecture, most likely through stacking interactions.
Increases of duplex stability upon the multiple incorpo-
ration of flexible aromatic base surrogates were probably
described first by Leumann and co-workers.[7b,9] In biphenyl-
modified DNA the two distal phenyl groups of a biphenyl–
biphenyl pair were found to be stacked on top of each other;
this arrangement may partly compensate for the energy cost
of planarization of the biphenyl ring systems and the
5Bn2·5’Bn2
5T2·5’T2
5A2·5’A2
5T2·5’A2
Bn
T
A
Bn
T
A
67.4
52.2
51.3
66.0
5’-CGGCAXXCGAGCGGC-3’
3’-GCCGTYYGCTCGCCG-5’
T
A
5Bn3·5’Bn2
5T3·5’T2
5A3·5’A2
5T3·5’A2
Bn
T
A
Bn
T
A
70.0
50.1
49.0
58.7
5’-CGGCAXXXCGAGCGGC-3’
3’-GCCGT YY GCTCGCCG-5’
T
A
[a] c=1 mm in 10 mm NaH2PO4, 0.1m NaCl, pH 7.0.
decreases of the duplex stability by DTM = 6–98C. This
significant destabilization appears plausible. Though intra-
strand stacking of the inner naphthyl unit may partially
compensate for the loss of hydrogen-bonding interactions,
simultaneous intrahelical alignment of the adenine and the
proximal naphthyl unit can probably occur only if one of the
bases adopts a syn orientation (Figure 2A, Figures S4 and
S5A in the Supporting Information). The outer naphthyl unit
of the binaphthyl base in duplexes such as 1Bn–4Bn will most
likely protrude into the unfavorable aqueous environment in
the major groove.
We next studied duplexes 5Bnn·5’Bnm (n = 0–3, m = 0–2),
which feature an increasing number of binaphthyl units
(Table 1). The binaphthyl nucleotide in a bulge position
(5Bn·5’, n = 1, m = 0, X = Bn) led to a duplex that was 6.18C
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Table 2: Fluorescence properties of binaphthyl-modified oligonucleoti-
des.[a]
[b]
[b]
Single strands
I/IB
Double strands
I/IB
binaphthyl
1Bn
2Bn
3Bn
4Bn
1
–
–
0.055
0.531
0.091
0.474
0.078
0.664
1.350
0.052
0.365
-
1Bn·1’A
2Bn·2’A
3Bn·3’A
4Bn·4’A
5Bn·5’
5Bn·5’Bn
5Bn·5’Bn2
5Bn2·5’Bn
5Bn2·5’Bn2
5Bn3·5’Bn2
0.099
0.217
0.050
0.075
0.160
0.327
0.744
1.092
2.419
3.227
5Bn
5Bn2
5Bn3
5’Bn
5’Bn2
–
[a] c=1 mm in 10 mm NaH2PO4, 0.1m NaCl, pH 7.0, 208C. [b] Relative
fluorescence based on the fluorescence intensity of 1,1’-binaphthyl at
l(emission)=380 nm and l(excition)=305 nm.
Figure 3. The influence of additional nucleotides X and Y on the
stabilities of duplexes 5Xn·5’Ym (X=Bn, T, or A; Y=Bn, T, or A; n=0–
3; m=0–2). Data obtained for biphenyl-modified duplexes (dashed
line)[9] is added for comparison.
of fluorescence upon multiple introduction of planar fluo-
rophores such as pyrene and perylenes.[3h,14] We speculate that
the first binaphthyl base serves as an insulator that protects
the second and third binaphthyl fluorophore from quenching
interactions with the pyrimidines.[15] This implies that the
binaphthyl chromophore experiences only little self-quench-
ing in this system.[16] Indeed, the experiments that involved
two or more interacting binaphthyl units revealed enhance-
ments of binaphthyl fluorescence upon hybridization
(Table 2, see also Figure S8B in the Supporting Information).
Duplexes 5Bnn·5’Bnm fluoresced with 50–150% higher inten-
sity than expected based on the sum of the fluorescence of the
corresponding single strands.
The purpose of this investigation was to explore torsion-
ally flexible, nonplanar base surrogates in DNA. At first
glance, the observed stabilization of a DNA duplex upon
successive introduction of multiple binaphthyl units may seem
surprising. However, the ground-state potential energy curve
of 1,1’-binaphthyl is flat in the region corresponding to a
dihedral angle between 608 and 1208.[10b] Thus, the binaphthyl
system may be well suited to adjust the two, flexibly linked
aromatic units for stacking interactions which may involve
both intrahelical and extrahelical partners. Of note, these
interactions do not lead to the self-quenching of fluorescence
as is frequently observed when planar aromatic base surro-
gates such as pyrenes are in contact.[3h,14] This behavior may
be of interest for the design of oligonucleotide assemblies
with light-harvesting properties.[17]
At present it remains unclear whether the DNA helix
induces axial chirality of binaphthyl stacks. Preliminary
modeling studies (Figure S5 in the Supporting Information)
suggest that both the R and the S forms can be accommo-
dated. Circular dichroism studies may be a useful means to
probe the chirality of the binaphthyl systems. However, this
would require modifications of the binaphthyl fluorophore in
order to avoid overlap with the absorption of the nucleobases.
The introduction of stable axial chirality through the incor-
poration of substituents in the 2- and 2’-positions would also
provide interesting opportunities. The resulting three-dimen-
sional chiral nucleobases could be useful tools in the
fluorescence-based diagnosis of the handedness of nucleic
perturbation of nucleobase–nucleobase stacking.[8a] By con-
trast, it is difficult to imagine planarization of the binaphthyl
residue investigated in this study. It is, thus, unlikely that the
distal naphthyl rings in 5Bn·5’Bn are in face-to-face contact.
This explains why the binaphthyl–binaphthyl pair destabilized
the duplex more efficiently (DTM = À5.28C) than a biphenyl–
biphenyl pair (DTM = À2.58C).[9] However, additional
binaphthyl units may result in intrastrand interactions
between the distal naphthyl rings within the major groove
(Figure 2B; Figure S5B in the Supporting Information).[13,3j]
These interactions involve larger surfaces than the stacked
phenyl rings in biphenyl base pairs, which may explain why
the TM increase upon introduction of one additional
binaphthyl pair (DTM = 7.88C) is higher than that upon
introduction of one additional biphenyl pair (DTM =
4.48C).[9] It is also feasible that the distal naphthyl units of
two binaphthyl bases interact in an edge-to-face fashion
(Figure S5C in the Supporting Information). Regardless of
the exact mechanism involved, we assume that the torsional
flexibility of the binaphthyl hinge facilitates stacking inter-
actions which can occur at both the interior and the exterior
of the DNA duplex.
The fluorescence properties also support the notion of
binaphthyl–binaphthyl interactions in DNA. The oligonu-
cleotides were excited at a wavelength of 305 nm. The
fluorescence properties were characterized by means of the
relative fluorescence I/IB (I, IB: fluorescence emission of
binaphthyl-modified oligonucleotides and free 1,1’-
binaphthyl, respectively). The investigation of oligonucleo-
tides 1Bn–4Bn revealed thymine and cytosine to be efficient
quenchers of binaphthyl fluorescence (90–95% quenching,
Table 2; see also Figure S8A in the Supporting Information).
By comparison guanine and adenine were inefficient (ca.
50%) quenchers. Interestingly, the incorporation of a second
or a third fluorophore in 5Bn2, 5Bn3, or 5’Bn2 led to a strong
enhancement of the fluorescence. For example, the oligonu-
cleotide 5Bn3 (I/IB = 1.350) was found to fluoresce with a 17-
fold higher intensity than oligonucleotide 5Bn (I/IB = 0.078).
This behavior is in contrast to the recently observed decreases
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Received: June 12, 2009
Published online: September 29, 2009
Keywords: binaphthyl · C-nucleosides · DNA · fluorescence ·
.
stacking interaction
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