Glucose–Nucleobase Pseudo Base Pairs: Biomolecular Interactions within DNA

Article abstract of DOI:10.1002/anie.201603510

Noncovalent forces rule the interactions between biomolecules. Inspired by a biomolecular interaction found in aminoglycoside–RNA recognition, glucose-nucleobase pairs have been examined. Deoxyoligonucleotides with a 6-deoxyglucose insertion are able to h

Full text of DOI:10.1002/anie.201603510

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Communications
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International Edition: DOI: 10.1002/anie.201603510
German Edition: DOI: 10.1002/ange.201603510
Noncovalent Interactions
Glucose–Nucleobase Pseudo Base Pairs: Biomolecular Interactions
within DNA
Empar Vengut-Climent, Irene Gꢀmez-Pinto, Ricardo Lucas, Pablo PeÇalver, Anna AviÇꢀ,
Cꢁlia Fonseca Guerra, F. Matthias Bickelhaupt, Ramꢀn Eritja, Carlos Gonzꢂlez, and
Juan C. Morales*
Abstract: Noncovalent forces rule the interactions between
biomolecules. Inspired by a biomolecular interaction found in
aminoglycoside–RNA recognition, glucose-nucleobase pairs
have been examined. Deoxyoligonucleotides with a 6-deoxy-
glucose insertion are able to hybridize with their complemen-
tary strand, thus exhibiting a preference for purine nucleobases.
Although the resulting double helices are less stable than
natural ones, they present only minor local distortions. 6-
Deoxyglucose stays fully integrated in the double helix and its
OH groups form two hydrogen bonds with the opposing
guanine. This 6-deoxyglucose-guanine pair closely resembles
a purine-pyrimidine geometry. Quantum chemical calculations
indicate that glucose-purine pairs are as stable as a natural T-A
pair.
glycoside antibiotics are a well-known family of RNA binders
which target the 16S rRNA in the small ribosomal subunit.
Apart from electrostatic forces and hydrogen bonds, solution
and X-ray structures of aminoglycosides with rRNA show
a singular biomolecular interaction, a monosaccharide–nucle-
obase stacking interaction [e.g., 2’-amino-2’-deoxyglucose
(ring I) of paromomycin stacks over guanine 1491;
Figure 1].[3]
N
oncovalent forces govern interactions among biomole-
cules, drug–target molecular recognition and assembly pro-
cesses. Hydrogen bonds, p–p stacking, van der Waals forces,
electrostatic forces, and hydrophobic interactions are
observed in RNA recognition by drugs such as macrolides,
tetracyclines,[1] and new designed RNA binders.[2] Amino-
Figure 1. a) Structure of paromomycin. b) Detail of the solution struc-
ture of paromomycin binding a 16S RNA model sequence. c) Drawing
of the glycoside-adenine 4108 pseudo base pair.
[*] Dr. E. Vengut-Climent, Dr. R. Lucas, Dr. P. PeÇalver, Dr. J. C. Morales
Department of Bioorganic Chemistry
Instituto de Investigaciones Quꢀmicas
CSIC—Universidad de Sevilla
Amꢁrico Vespucio 49, 41092 Sevilla (Spain)
E-mail: jcmorales@ipb.csic.es
Recently, we have studied sugar–DNA stacking interac-
tions using a self-complementary CGCGCG sequence with
the carbohydrates directly linked to the 5’-end of DNA. We
observed stacking of mono- and disaccharides on top of the
terminal DNA base pairs, which stabilized the duplex
between À0.5 to À1.8 kcalmolÀ1.[4] Stacking of sugars on top
of the guanine tetrad of a DNA G-quadruplex was also
characterized.[4b]
A second singular biomolecular interaction found when
paramomycin binds rRNA is a glycoside-adenine pseudo base
pair (Figure 1c).[3] Two hydrogen bonds are formed between
ring I of paromomycin and A1408. Inspired by this interaction
we decided to study the possible formation of glucose-
nucleobase pairs. Since monosaccharides can stack on DNA
bases and possess OH groups capable of making hydrogen
bonds at the edge of their coinlike structure, like natural bases
(Figure 2a), we placed a potential glucose-nucleobase pair
inside a DNA double helix to investigate its properties
(Figure 2b). This model system also allows us to study
possible sugar-sugar pairs. The only non-aromatic nucleo-
bases reported previously are Leumannꢀs phenyl cyclohexyl
interstrand base[5] and Kashidaꢀs isopropylcyclohexane and
methylcyclohexane DNA base insulators.[6]
Dr. I. Gꢂmez-Pinto, Prof. C. Gonzꢃlez
Instituto de Quꢀmica Fꢀsica “Rocasolano”, CSIC
28006 Madrid (Spain)
Dr. R. Lucas, Dr. P. PeÇalver, Dr. J. C. Morales
Department of Biochemistry and Molecular Pharmacology
Instituto de Parasitologꢀa y Biomedicina, CSIC, Parque Tecnolꢂgico
Ciencias de la Salud
18016 Armilla, Granada (Spain)
Dr. A. AviÇꢂ, Prof. R. Eritja
Instituto de Quꢀmica Avanzada de CataluÇa (IQAC), CSIC
CIBER—BBN Networking Centre on Bioengineering, Biomaterials
and Nanomedicine, 08034 Barcelona (Spain)
Dr. C. Fonseca Guerra, Prof. Dr. F. M. Bickelhaupt
Department of Theoretical Chemistry and Amsterdam Center for
Multiscale Modeling, Vrije Universiteit Amsterdam
1081 HV Amsterdam (The Netherlands)
Prof. Dr. F. M. Bickelhaupt
Institute of Molecules and Materials (IMM), Radboud University
6525 AJ Nijmegen (The Netherlands)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201603510.
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Table 1: Melting temperature (Tm) for DNA duplexes containing T*, glc,
and 6dglc, and GNA duplexes containing 6dglc.
DNA duplexes
5’-d(GATGACXGCTAG)[a,b]
3’-d(CTACTGYCGATC)
X-Y
Tm [8C]
X-Y
Tm [8C]
X-Y
Tm [8C]
T*-A
T*-T
T*-C
T*-G
T*-T*
37.7
32.8
32.0
35.6
31.1
glc-A
glc-T
glc-C
glc-G
glc-glc
30.6
28.5
28.7
31.3
29.6
6dglc-A
6dglc-T
6dglc-C
6dglc-G
6dglc-6dglc
33.2
29.9
29.9
32.7
32.0
GNA duplexes
3’-TAAAATTTAXATTATTAA[b,c]
2’-ATTTTAAATYTAATAATT
X-Y
X-Y
Tm [8C]
Tm [8C]
T-A
T-T
57.3
48.0
A-6dglc
T-6dglc
6dglc-T
6dglc-6dglc
45.4
37.4
38.7
43.0
[a] The natural DNA duplex containing X-Y=T-A results in a Tm value of
47.98C. [b] Conditions for DNA duplexes: 10 mm NaH2PO4, 150 mm
NaCl, pH 7.0. For GNA duplexes: 10 mm NaH2PO4, 200 mm NaCl,
pH 7.0. Estimated errors are: Æ0.48C (in DNA, except for 6dglc-6dglc:
Æ1.08C) and Æ1.08C (GNA). Average value of three experiments
measured at 1.2 mm conc (DNA) and 0.7 mm conc (GNA). [c] GNA
monomers in italics.
Figure 2. Description of the carbohydrate derivatives under study.
a) CPK models of thymine and glucose. b) Schematic drawing of
a DNA double helix containing a glycoside-nucleobase pair. c) Struc-
tures of the two sugar units prepared, (S)-2,3-dihydroxypropyl glucose
(glc) and (S)-2,3-dihydroxypropyl 6-deoxyglucose (6dglc), thymidine
(T), (S)-3,4-dihydroxybutyl thymine or flexible T (T*), and glycol T
(T-GNA).
T leads to a 10.2–15.98C decrease in stability (Table 1). The
decrease in stability of DNA containing single or multiple
acyclic nucleosides has been previously reported.[7] Secondly,
the DNA duplexes with glc and 6dglc opposite to the four
natural nucleosides were destabilized in comparison to the
duplexes with T-A and T*-A. Considering the penalty of the
flexible linker, destabilization of glc pairs compared to T*-A
ranges from 6.4 to 9.28C. Interestingly, the presence of the
more apolar 6dglc improved the DNA stability, when
compared to glc, by 1.2–3.98C. Still, the more stable pair,
6dglc-A, led to a DNA duplex which is 4.58C less stable than
that with T*-A, and 15.78C less stable than that with T-A. The
larger volume of the pyranose ring, in comparison with an
aromatic ring, may distort the nearby DNA base pairs and
provoke this decrease in DNA stability. Thirdly, we observed
certain selectivity for glc-nucleobase and 6dglc-nucleobase
pairs. Sugar-purine pairs were more stable than sugar-
pyrimidine pairs (from 1.9 to 3.38C). This difference may be
a consequence of direct hydrogen bonding between the OH
groups of glc and 6dglc and the donor and acceptor groups in
A and G. Alternatively, purines may be preferred in front of
glucose in the sequence just for the better stacking as
observed in abasic sites,[8] but the NMR spectroscopy and
theoretical calculations shown below indicate that hydrogen
bonding between glc and 6dglc with A and G is possible.
Fourthly, the stability of DNA duplexes containing sugar-
sugar pairs ranges from 29.6 to 32.38C. Unexpectedly, pairs
containing two flexible spacers and two bulky pyranose rings
do not show further DNA destabilization in comparison to
sugar-natural nucleobase pairs. For example, a 6dglc-6dglc
pair is as stable as a 6dglc-purine pair.
Glucose (glc) was linked to the phosphodiester backbone
of DNA through a flexible glycerol linker through its
anomeric position. Thus, we prepared the DMT-glucose
phosphoramidite derivative 9 (Scheme 1) for introduction at
the required position of the oligonucleotide, similar to
a standard natural DNA base phosphoramidite. To modulate
the high polarity of glucose, we also prepared the 6dglc
amidite 10. A flexible T (T*) was synthesized for comparison
of glc with a pyrimidine base in the same environment
(Figure 2c; see Figure S1 in the Supporting Information).
We then measured thermal denaturation of DNA
duplexes containing our modifications. Firstly, the introduc-
tion of a flexible linker, such as in T*, with respect to a natural
Scheme 1. Synthesis of the carbohydrate DMT phosphoramidites.
Glycosyl trichloroacetimidate donors were used as starting material.
Reagents and conditions: a) TMSOTf, CH2Cl2 for glc; BF3·OEt2, CH2Cl2
for 6dglc; b) AcOH/H2O (4:1), 808C; c) DMTCl, DMAP, CH2Cl2;
d) DIPEA, CH2Cl2. DIPEA=diisopropylethylamine, DMAP=4-(N,N-
dimethylamino)pyridine, DMT=4,4’-dimethoxytrityl, Tf=trifluoro-
methanesulfonyl, TMS=trimethylsilyl.
We also incorporated glc and 6dglc into a glycerol nucleic
acid (GNA) double helix. GNA strands have an acyclic
backbone of propylene glycol nucleosides which incorporate
2
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the natural nucleobases in the strand and
are connected by phosphodiester bonds
(Figure 2c).[9] In this context, both natu-
ral bases and our sugar modifications are
linked through flexible linkers to the
skeleton and no energetic penalty is
expected. The Tm values measured
showed that the GNA duplex with an
A-6dglc pair was 11.98C less stable than
with T-A (Table 1) and only 2.68C less
stable than with a mismatched T-T. It is
quite notable that the selectivity between
T-A and T-T pairs (9.38C) is similar to
that between 6dglc-A and 6dglc-T pairs
(6.7–8.08C). Lastly, a 6dglc-6dglc pair
results in a GNA duplex stability of
438C, thus pointing to the formation of
hydrogen bonds between the OH groups
of each 6dglc unit.
We next determined the three-dimen-
sional high-resolution structure of DNA
duplexes containing
a 6dglc-G and
a 6dglc-T pair using restrained molecular
dynamics methods based on experimen-
tal NMR distance constraints (Figure 3).
The exchangeable proton region of the
NMR spectra exhibited 11 imino proton
signals between d = 12.5 and 14.5 ppm,
thus indicating the formation of a duplex
structure with Watson–Crick base pairs
(see Figure S4). Additional imino proton
signals are observed in the d = 10–11 ppm
region corresponding to the nucleotide
Figure 3. Solution structure of the helix 6dglc-G and helix 6dglc-T. a) Sequences of the helix
6dglc-G. b) Refined solution structure of the helix 6dglc-G and zoom views of the 6dglc-G
pair. c) NOE interactions between 6dglc and its 5’-neighboring base C18 and its 3’-
neighboring base pair G20-C5. d) NOESY trace showing key NOEs with the methyl group of
6dglc. e) Sequences of helix 6dglc-T. f) Refined solution structure of helix 6dglc-T and zoom
located opposite to the carbohydrate. views of the 6dglc-T pair. g) NOE interactions between 6dglc and its 5’-neighbouring base
C17, and with its 3’-neighboring base pair G19-C6 and opposite base T7. h) NOESY trace
showing key NOEs with the methyl group of 6dglc. Color code: sugar and spacer (purple),
nucleobases (green and blue) and surrounding natural base pairs (light blue).
Full proton assignment of the DNA and
sugar units was performed with only
a few exceptions (see Tables S1 and S2).
DNA chemical-shift differences between
the conjugates and the natural DNA
control duplexes are limited to the surroundings of the
carbohydrate moieties, thus indicating the overall duplex
structure is not distorted (see Figure S5).
structures, these hydrogen bonds are H1 G–O4 6dglc and
HN2 G–O3 6dglc (Figure 3b). The other structures show
different conformers, including the pattern obtained in the
quantum calculations (see below). All orientations are
experimentally supported by a number of intra- and inter-
strand NOEs, like those between the methyl group of 6dglc
with H5 and H6 C18, with amino protons of C5, and with
H1 G20 (Figure 3c). In the helix 6dglc-T the monosaccharide
forms only one hydrogen bond with the opposing T. In most
structures (7 out of 10), this hydrogen bond is H3 T–O4 6dglc
(Figure 3 f), and in the other cases the hydrogen bond is HO4
6dglc–O2 T. The orientation is supported by NOEs, for
example, between the methyl group of 6dglc with methyl and
H6 T7; with H1 and H8 G19; and with H5 and H6 C17
(Figure 3g). The formation of an extra hydrogen bond, when
comparing 6dglc-G and 6dglc-T, may contribute to the
enhanced thermal stability and it may explain the observed
selectivity for purines.
The 3D structures obtained are B-form helices without
global distortions (Figure 3; see Figures S7 and S8). The
carbohydrates and the nucleobases (G or T) located in the
opposite position remain intercalated between the surround-
ing base-pairs maintaining extensive contacts at both sides. As
a consequence, a large number of NOE crosspeaks (see
Table S3) between the linker and the carbohydrate protons
with the DNA are observed. In all cases the double helices are
slightly unwound and the rise between flanking residues is
increased, as usually occurs in intercalation complexes.
The structures of helix 6dglc-G and helix 6dglc-T are
deposited in the PDB (2N9Fand 2N9H, respectively). 6dglc is
well located opposite to both guanine (Figure 3b) and
thymine (Figure 3 f), thus orienting its alpha face towards its
3ꢀ-neighboring nucleobase and its methyl group towards the
major groove. In the helix 6dglc-G the sugar-nucleobase pair
forms two hydrogen bonds. In six of the ten resulting
The pairing properties of glc and 6dglc in the gas phase
and water were investigated quantum chemically by means of
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dispersion-corrected density functional theory (DFT) at the
BLYP-D3(BJ)/TZ2P level of theory.[10] The binding energies
(DE) of the Watson–Crick base pairs A-T and G-C agreed
Interestingly, sugar-sugar base pairs show similar bond
energies to that of sugar-pyrimidine base pairs. One, two, and
three hydrogen bonds are formed in 6dglc-6dglc, 6dglc-glc,
and glc-glc, respectively, where the OH groups involved can
act as either hydrogen-bond donors or acceptors (Figure 4d).
In contrast to the experimental data found for DNA, the
6dglc-6dglc pair appears to be less stable than the glc-glc base
pair. These differences may be ascribed to interactions with
the surrounding bases,[11] which are not considered in the
present calculations.
In conclusion, we have shown glycoside-nucleobase pairs
form within a DNA double helix. They cause some destabi-
lization of either a DNA or GNA duplex but they display
selective pairing with purines versus pyrimidines. This selec-
tivity can be explained by the formation of hydrogen bonds
between either glc or 6dglc with the natural bases as shown by
quantum chemical calculations and NMR studies. Moreover,
6dglc stacks within the interior of a duplex when paired with
either G or Tand does not stick out of the helix seeking better
hydration. These 6dglc-G and 6dglc-T pairs infer only minor
distortion in the double-helix structure.
Table 2: Hydrogen-bond energies (in kcalmolÀ1) of sugar-base pairs in
the gas-phase (DEgas) and in aqueous solution (DEwater).[a]
X-Y
DEgas
DEwater
X-Y
DEgas
DEwater
A-T
À18.5
À23.8
À10.5
À16.7
À12.9
À8.3
À9.4
À10.5
À6.1
À10.5
À6.7
À4.1
À7.6
G-C
À34.0
À23.3
À15.4
À16.7
À17.7
À12.7
À13.5
À12.2
À9.5
6dglc-G
6dglc-T
6dglc-A
6dglc-C
6dglc-6dglc
6dglc-glc
glc-G
glc-T
glc-A
glc-C
glc-glc
À10.7
À5.1
À8.7
À11.4
[a] Calculated at BLYP-D3(BJ)/TZ2P using COSMO to simulate aqueous
solution.
with those reported in literature (Table 2).[11] Sugar-purine
pairs show greater hydrogen-bonding energy than any other
combination for both for glc and 6dglc. In fact, the G-6dglc
pair shows greater energy of bonding than a natural A-T base
pair, with two hydrogen-bonds between the OH3 and OH4 of
=
6dglc with the NH1 and C O, respectively, of G (Figure 4).
Acknowledgments
We thank the Ministerio de Economꢁa y Competitividad
(CTQ2011-15203-E, CTQ2012-35360, CTQ2014-52588-R,
BFU2014-52864-R), the Netherlands Organization for Scien-
tific Research (NWO-CW and NWO-EW), and the National
Research School Combination—Catalysis (NRSC-C) for
financial support. E.V.C. thanks Ministerio de Educaciꢂn,
Cultura y Deporte for a FPU fellowship and Cost Action
CM1005 for a STSM grant.
Keywords: DNA · hydrogen bonds · NMR spectroscopy ·
noncovalent interactions · nucleobases
Figure 4. A-T, G-6dglc, 6dglc-T, and glc-glc pairs calculated at BLYP-
D3(BJ)/TZ2P using COSMO to simulate aqueous solution. Hydrogen
bonds are shown in green.
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Two hydrogen bonds are also observed for A-6dglc, G-glc,
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=
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4
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Received: April 11, 2016
Revised: May 19, 2016
Published online: && &&, &&&&
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Communications
Noncovalent Interactions
New lego pieces: The formation of a glu-
cose–nucleobase pseudo base pair is
proposed as a new type of biomolecular
interaction. When formed within a DNA
double helix the high-resolution structure
shows only a minor distortion. These
DNA duplexes are less stable than natural
ones, but glucose shows preference for
binding purine nucleobases. Moreover,
quantum chemical calculations indicate
that glucose–purine pairs are as stable as
a natural T–A pair.
E. Vengut-Climent, I. Gꢁmez-Pinto,
R. Lucas, P. PeÇalver, A. AviÇꢁ,
C. Fonseca Guerra, F. M. Bickelhaupt,
R. Eritja, C. Gonzꢂlez,
J. C. Morales*
&&&& — &&&&
Glucose–Nucleobase Pseudo Base Pairs:
Biomolecular Interactions within DNA
6
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