Cooperative self-assembly of adenosine and uridine nucleotides on a 2D synthetic template

Article abstract of DOI:10.1002/anie.200600450

(Figure Presented) Double plane: Base pairing mediates sterically induced, cooperative self-assembly of complementary nucleotides on a template formed from amphiphilic bis(Zn^II-cyclen) derivatives ordered on thiolated surface. Real-time monitoring of binding events proved precise harboring of equal amounts of A and U nucleotides from their arbitrary combinations in solution into planar bilayers (see picture).

Full text of DOI:10.1002/anie.200600450

Communications
Self-Assembly
DOI: 10.1002/anie.200600450
Cooperative Self-Assembly of Adenosine and
Uridine Nucleotides on a 2D Synthetic
Template**
Dmitry S. Turygin, Michael Subat, Oleg A. Raitman,
Vladimir V. Arslanov, Burkhard König,* and
Maria A. Kalinina*
This paper describes a two-dimensional chemical system in
which a divalent “template” guides and controls the stepwise
and cooperative self-assembly mediated by base pairing of
adenosine and uridine nucleotides.
Multiple hydrogen bonding and base pairing constitute
one of the most widely studied classes of noncovalent
interactions in supramolecular chemistry.[1] The precision
with which nature utilizes complementary weakbonding to
guide self-assembly of complex structures remains a fascinat-
ing challenge for surface chemistry that aims to develop novel
approaches to interfacial sensing and nanofabrication.[2] To
date, attempts to use base pairing as a basis for planar
molecular-recognition systems have focused on self-assem-
bled monolayers (SAMs)[3,4] or Langmuir monolayers[5] that
are formed from compounds bearing nucleobases or their
synthetic analogues. Although exceptionally useful in the
precise vertical alignment of oligo/polynucleotides on solid
supports,[6] the SAM-based methods are unsuitable for lateral
tailoring of recognition surfaces with different types of bases.
This is mostly because of steric hindrance and phase
separation of monolayer constituents.[3,7] On the other hand,
Langmuir monolayers enable fine-tuning of steric conditions
in highly ordered films comprised of different entities at air/
water interfaces,[8] but their practical applicability is severely
limited. Herein, we use a novel surface-design scheme that
combines the advantages of SAM-based and Langmuir-
Blodgett (LB) monolayer approaches. This allows for precise
harboring of arbitrary combinations of complementary
nucleotides in planar films through sterically induced, coop-
[*] M. Subat, Prof. Dr. B. König
Institut für Organische Chemie
Universität Regensburg
Universitätstrasse 31, 93040 Regensburg (Germany)
Fax: (+0049)941-943-4575
E-mail: burkhard.koenig@chemie.uni-regensburg.de
D. S. Turygin, Dr. O. A. Raitman, Prof. V. V. Arslanov,
Prof. M. A. Kalinina
Department of Physical Chemistry of Supramolecular Systems
Frumkin Institute of Physical Chemistry and Electrochemistry RAS
31 Leninsky prospect, Moscow 119991 (Russia)
Fax: (+7)095-952-53-08
E-mail: pcss_lab@mail.ru
[**] We thank Prof. Bartosz A. Grzybowski for valuable discussion. This
work was supported by RFBR (grant no. 05-03-32195).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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erative self-assembly on a surface presenting divalent bis-
(ZnII–cyclen) complexes.[9–12] These complexes have been
previously used for selective recognition of thymidine and
uridine bases in polynucleotides and natural DNA.[13] Fur-
thermore, they have a use as highly efficient divalent
receptors for thymidine and uridine nucleotides that interact
with the bis-cyclic host through simultaneous binding of
terminal phosphate and imide groups to complementary
macrocyclic fragments.[14] In our system, the selective forma-
tion of bis(ZnII–cyclen)-nucleotide aggregates promotes
cooperative nucleotide self-assembly on a recognition sur-
face.
We ordered amphiphilic bis(ZnII–cyclen) derivatives
(hereafter, ZnII–BC) into a planar matrix through LB transfer
of ZnII–BC monolayers from an aqueous subphase onto a
gold-coated surface covered with a loosely packed SAM of
octanethiol (Figure 1). This simple combination of SAM and
Figure 2. SPR sensograms for stepwise adsorption of a 5’-ATP/5’-UTP
binary combination on a SAM-ZnII–BC surface. a) The experiment
started by probing with UTP (0.02 mm) followed by subsequent
addition of ATP (0.02 mm) and of UTP (0.02 mm), b) the “vice versa”
subsequent binding of ATP (0.02 mm) and UTP (0.02 mm) finalized by
probing with UDP (0.05 mm); pH 7.5.
UTP (a) and adsorption of ATP, followed by UTP and
UDP(b)).
Initially, ZnII–BC surfaces responded slowly to both types
of nucleotides. The first-stage binding translated into an SPR
maximal response, Da1, that falls within a range of 1.8–2.7
angle min;[16] the absolute values of Da1 increased with the
molecular weight of the measured nucleotides.[15] In addition,
the kinetics and values of Da1 determined for 5’-AXPs were
similar to those measured for similar 5’- UXPs (here, 2.5–2.7
angle min for UTP and ATP).
Figure 1. Schematically drawn structure of a SAM-supported mono-
layer of ZnII–BC on a gold-coated surface.
LB techniques preserves a uniform order of the precursor
monolayer and gives a stable, interdigitated bilayer with
macrocyclic fragments exposed to the solution. According to
our preliminary studies, ZnII–BC immobilized in such a film is
capable of binding nucleotide constituents modeled with
uracil and an inorganic phosphate dianion while being
inactive to adenine or monoanionic phosphates (for details
see the Supporting Information).[15] The nucleotide assembly
on functionalized SAM/LB plates was investigated in aqueous
solutions of monovalent adenosine 5’-mono-, di- or triphos-
phates (hereafter, 5’-AXPs, where X = M (mono), D (di), or T
(tri)) and/or divalent uridine 5’-mono-, di- or triphosphates
(5’-UXPs, where X = M (mono), D (di), or T (tri)) at pH 7.5
through surface plasmon resonance (SPR) as a most appro-
priate tool for real-time monitoring of binding events.
After the completion of initial adsorption, similar probes
of complementary nucleotides (0.02 mm) were added. The
kinetics of secondary binding of either 5’-AXP or 5’-UXP at
the surface with an already-adsorbed complementary partner
was very different from that of initial recognition—the SPR
signal increased rapidly and reached its maximal value Da2,
which was twice that of Da1. Again, the Da2 value varied from
3.6 to 5.4 angle min in proportion to the nucleotideꢀs
molecular weight, and the magnitudes of responses to 5’-
AXP and 5’-UXP were similar (5.4 and 5.3 angle min for ATP
and UTP, respectively). Importantly, because the magnitude
of the SPR signal is proportional to the amount of adsorbed
analyte, it appears that the initial binding of one molecule of
either monovalent 5’-AXP or divalent 5’-UXP by ZnII–BC
film promotes further assembly of not one but two comple-
mentary molecules.
The SPR sensograms in Figure 2a,b illustrate typical
kinetics of the stepwise assembly of 0.02 mm 5’-AXPs and 5’-
UXPs for different orders of nucleotide addition (i.e., UTP
probing followed by the subsequent addition of ATP and
Furthermore, when equilibrated after secondary binding,
the sensing surfaces were still capable of specific recognition;
the films responded to the nucleotides that were comple-
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mentary to the one bound at the second stage (Figure 2a).
complementary partners. The effect also points to the
mediating role of base pairing in secondary recognition of
complementary nucleotides—it is hindered when comple-
mentary H-bonding is “switched off”.
Moreover, maximal third-stage responses Da3 were close to
Da1, that is, the efficiency of final adsorption was comparable
with that observed at the initial stage. On the other hand,
addition of a nucleotide containing a base similar to that used
in second-stage binding caused no significant increase in the
SPR signal even at increasing concentrations (Figure 2b). The
specificity of the third-stage responses and their absolute
values suggest that this stage proceeds with complementary
recognition of incoming nucleotides (UTP on Figure 2a) by
only half of the potentially available complementary partners
already present on the surface (ATP on Figure 2a).
The secondary recognition of adenosine phosphates was
also inhibited by preliminary adsorption of UMP—the small-
est divalent nucleotide studied herein (Figure 3b).[18] The
distance between cyclic “heads” of ZnII–BC is presumably
well matched to UMPꢀs molecular geometry thus allowing for
simultaneous intramolecular coordination of phosphate and
imide groups to the neighboring macrocycles. The surface
with bound UMP becomes inactive with respect to other
incoming nucleotides as both macrocyclic moieties in ZnII–
BC are occupied and therefore, the UMP nucleobase
involved in this divalent binding mode is unavailable for
base pairing.
To understand the mechanism of nucleotide assembly, we
make several observations related to the inhibition of
secondary binding events. Firstly, as illustrated by Figure 3a,
These observations support a mechanism involving step-
wise self-assembly of complementary nucleotides at ZnII–BC
monolayers (Figure 4). Specifically, irrespective of the nucle-
Figure 4. Schematic diagrams illustrating the possible mechanism of
the stepwise self-assembly of complementary nucleotides on a SAM-
ZnII–BC template (one ZnII–BC unit is shown). a) Phosphate attach-
ment of a nucleotide to the one of ZnII–cyclen units, b) base pairing
accompanied by the guiding of terminal phosphate of complementary
nucleotide to the opposite ZnII–cyclen, c) firm attachment of the
complementary nucleotide to ZnII–BC and dissociation of the base
pair, d) base pairing of incoming nucleotides with complementary
partners already immobilized on the template.
Figure 3. Inhibition of secondary recognition of 5’-ATP at SAM-ZnII–BC
sensing film. a) Initial adsorption of 5’-UDP (0.02 mm) at pH 7.5
followed by subsequent addition of adenine (0.05 mm; pH 7.9) and 5’-
ATP (0.02 mm), b) the assembly of 5’-UMP (0.02 mm) followed by the
probing with 5’-ATP (0.02 mm).
otide used, the first binding event is mediated by the
coordination of the terminal phosphate to one of the
“heads” of the ZnII-BC template (Figure 4a). The geometry
of the ZnII–BC molecule prevents simultaneous divalent
binding of 5’-UXPs with a distance between the base and
terminal phosphate longer than that in 5’-UMP. These first-
step interactions, however, cause steric crowding at the
opposite ZnII–cyclen, thus shielding the free macrocycle
from similar nucleotides and hindering their binding to the
same ZnII–BC molecule.
Incoming complementary nucleotides recognize the
already bound partner through base pairing.[19] Nucleotide
coupling results in a spatial arrangement of the interacting
components that favors simultaneous orientation (“guiding”)
of the terminal phosphate of a complementary nucleotide to
the protective binding of adenine to the ZnII–BC monolayer
with initially adsorbed 5’-UDP inhibited further assembly of
5’-ATP on the surface. Importantly, the response, Da2, to
adenine (which does not interact itself with ZnII–BC) was
almost exactly three-times lower than Da1 for UDP. As
adenineꢀs molecular weight is also three-times lower than that
of UDP, the registered signal difference corresponds to a 1:1
UDP–adenine binding ratio. The inhibitory effect of this
binding on further 5’-AXP recognition suggests that phos-
phate coordination is the first-stage binding mode even for
potentially divalent 5’-UXPs (except for UMP, which is
discussed below); moreover, the immobilized nucleotides
are well preorganized for the interactions with suitable
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the free “head” of the ZnII–BC molecule (Figure 4b). The
cooperative action of the template and both nucleotides is,
most likely, assisted by base stacking. Although the base
stacking interactions stabilize the ordering layer significantly,
the energetic contribution of hydrogen bonding is rather
small compared with the phosphate-anion coordination.
Therefore, dissociation of the base pair, exposing the hydro-
gen-bond donor and acceptor sites to the solution, is expected
to be in equilibrium (Figure 4c). Disengaged bases, in turn,
form complementary pairs with other incoming nucleoti-
des.[20] This chain of consecutive interactions results in the
formation of a bilayer structure that harbors equal amounts of
complementary nucleotides (Figure 4d).
Close agreement between maximal SPR responses registered
for one-step and stepwise modes of assembly indicates that
constant amounts of nucleotide bind to the surface irrespec-
tive of the procedure used. Some of the differences between
Daone step and Damultistep may be attributed to steric crowding at
the interface in more concentrated mixtures. Such crowding
results in the formation of structures that are not-so-
rigorously defined, presumably because some base pairs
between the nucleotide layer attached to the template and the
complementary top layer are uncompleted. Furthermore,
equal SPR signals measured in subsequent probing with
individual nucleotides in Figure 5 prove the alteration of the
binding mode in the course of self-assembly; when the ZnII–
BC template is saturated with bound nucleotides and a
bottom layer is formed, further completion of the bilayer
structure proceeds through 1:1 base recognition.
In summary, we described sterically induced cooperative
assembly of complementary nucleotides progressing through
the chain of consecutive mono- and divalent interactions on a
surface presenting artificial ZnII–BC receptors. We believe
that the approach utilized herein might be extended to other
types of planar patterns of complementary nucleotides, as
well as for the preparation of other artificial systems
preorganized for efficient molecular recognition and further
bottom-up self-assembly of synthetic molecules containing
suitable fragments.
The above mechanism suggests that nucleotide self-
assembly is independent from the formation path—that is,
stepwise recognition of complementary nucleotides in an
arbitrary order as well as their one-step self-assembly from an
equimolar mixture should give the same nucleotide pattern
on ZnII–BC surfaces. To prove this assumption, we studied
both continuous and interrupted adsorption of ATP/UTP
equimolar mixtures (0.02 mm of each nucleotide) on ZnII–BC
templates. One-step ATP/UTP adsorption translated into a
maximal increase in the SPR signal Daone step = 9.0 angle min
(data not shown; an SPR curve is given in the Supporting
Information). This value is more than twofold greater when
compared with Da = 3.9 angle min, which was measured for
the adsorption of ATP from a solution with a double
concentration of nucleotide (0.04 mm).[15] This correlates
well to Damultistep = 10.4, which was determined from Figure 2a
for the stepwise binding of the ATP/UTP combination.
Figure 5 describes interrupted adsorption of a similar
mixture, followed by stepwise surface probing with ATP
(0.02 mm) followed by UTP (0.02 mm) solutions. The ATP/
UTP mixed solution was replaced by one of ATP (0.02 mm)
Experimental Section
All nucleotides (adenosine 5’-monophosphate, adenosine 5’-diphos-
phate disodium salt hydrate, adenosine 5’-triphosphate disodium salt
hydrate, uridine 5’-monophosphate disodium salt hydrate, uridine 5’-
diphosphate disodium salt hydrate, and uridine 5’-triphosphate
trisodium salt hydrate) are of analytical-reagent grade and were
obtained from Acros Organics (Belgium). Nucleotides and organic
bases (uracil and adenine) were dissolved in water that was deionized
to 16MWcm resistivity and preliminarily adjusted to pH 7.5 by the
addition of a small amount of sodium hydroxide; these solutions were
used for SPR measurements immediately after their preparation.
Platform preparation: TF-1 glass supports covered with a Cr
adhesion sublayer (5 nm) and a polycrystalline Au layer (50 nm)
supplied by Analytical-mSystem were modified by immersion into an
absolute ethanol solution of octanethiol (1 mm) for 2 min. The
when Da reached 6.5 angle min greater than 1= Damultistepffi5.2
2
angle min. This value assumes that more than half of the
nucleotides that constitute the final bilayer were already
immobilized on a surface. After the completion of ATP
binding, UTP (0.02 mm) was added. We observed almost
equal SPR maximal signals for individual solutions; an overall
increase in the SPR signal Damax amounted to 9.4 angle min.
monolayers of ZnII–BC were spread from 10ꢀ5
m chlorophorm
solution onto basic subphase with pH 8.52, compressed to
17 mNmꢀ1, and vertically transferred (the down-stroke mode of
transfer was applied) onto thiolated support at a constant speed of
0.5 mmminꢀ1
.
SPR monitoring: The SPR Kretschmann-type spectrometer
Biosuplar-2 (Analytical-mSystem; a light-emitting diode light source
l = 670 nm) equipped with
a
peristaltic pump (flow rate
0.3 mLminꢀ1) was used for kinetic monitoring; freshly prepared
solutions were added in 15 mL portions to the pump vessel when the
previous portion was nearly all used. The SPR cell was rinsed with
pure water for 15–20 min prior to the addition of each next probe.
Other experimental details are given in the Supporting Informa-
tion.
Figure 5. SPR sensogram for the interrupted adsorption of 5’-ATP/5’-
UTP equimolar mixture (0.02 mm of each nucleotide) replaced by ATP
(0.02 mm) at Da=6.5 angle min and completed with the addition of
UTP (0.02 mm).
Received: February 2, 2006
Revised: April 25, 2006
Published online: July 17, 2006
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Communications
trometry, and MS for the final and intermediate products, the
formation procedure for Langmuir monolayers and the LB
monolayer of ZnII–BC, and surface pressure–area isotherms.
Additionally, cyclic voltammagram (CVA) data on SAM and
SAM/ZnII–BC films with an estimated surface coverage and
SPR data on the adsorption of other nucleotide combinations
that are not described in the main text are also included in the
Supporting Information.
Keywords: base pairing cooperativity · macrocycles ·
nucleobases · self-assembly · thin films
.
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[15] See the Supporting Information for details of the synthetic
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