Building blocks for recognition-encoded oligoesters that form H-bonded duplexes

Article abstract of DOI:10.1039/c8sc04896g

Competition from intramolecular folding is a major challenge in the design of synthetic oligomers that form intermolecular duplexes in a sequence-selective manner. One strategy is to use very rigid backbones that prevent folding, but this design can preju

Full text of DOI:10.1039/c8sc04896g

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Building blocks for recognition-encoded
oligoesters that form H-bonded duplexes†
Cite this: DOI: 10.1039/c8sc04896g
*
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Filip T. Szczypinski
and Christopher A. Hunter
´
Competition from intramolecular folding is a major challenge in the design of synthetic oligomers that form
intermolecular duplexes in a sequence-selective manner. One strategy is to use very rigid backbones that
prevent folding, but this design can prejudice duplex formation if the geometry is not exactly right. The
alternative approach found in nucleic acids is to use bases (or recognition units) that have different
dimensions. A long-short base-pairing scheme makes folding geometrically difficult and is compatible
with the flexible backbones that are required to guarantee duplex formation. A monomer building block
equipped with a long hydrogen bond donor (phenol, D) recognition unit and a monomer building block
equipped with a short hydrogen bond acceptor (phosphine oxide, A) recognition unit were prepared
with differentially protected alcohol and carboxylic acid groups. These compounds were used to
synthesise the homo and hetero-sequence 2-mers AA, DD and AD. 19F and 31P NMR experiments were
used to characterize the assembly properties of these compounds in toluene solution. AA and DD form
a stable doubly-hydrogen-bonded duplex with an effective molarity of 20 mM for formation of the
second intramolecular hydrogen bond. AD forms a duplex of similar stability. There is no evidence of
intramolecular folding in the monomeric state of this compound, which shows that the long-short base-
pairing scheme is effective. The ester coupling chemistry used here is an attractive method for the
synthesis of long oligomers, and the properties of the 2-mers indicate that this molecular architecture
should give longer mixed sequence oligomers that show high fidelity sequence-selective duplex formation.
Received 2nd November 2018
Accepted 3rd January 2019
DOI: 10.1039/c8sc04896g
rsc.li/chemical-science
It is clear that duplex formation is not restricted to the
precise molecular structure found in DNA and RNA. A range of
nucleic acid analogues have been prepared in which the phos-
phate diester,9–11 the bases,7,12–15 and the sugar have been
1 Introduction
1.1 Background
Two sequence-complementary strands of nucleic acid will form
a stable duplex due to hydrogen bonding interactions between
the bases. This supramolecular structure was immediately rec-
ognised to provide a plausible mechanism for information
transfer between a template strand and a copy in the key bio-
logical processes of replication, translation and transcription,
where the sequence of the copy is organised by the same base-
pairing interactions that lead to duplex formation.1,2 These
copying processes are currently unique to nucleic acids and
represent the molecular basis for the evolution of life on this
planet. Synthetic systems that form duplexes in the same way
are therefore likely to provide a platform for template-directed
synthesis of mixed sequence oligomers, and ultimately to the
application of directed evolution for the discovery of new
functional non-biological molecules.3–8
replaced,16–22 and all of these oligomers form stable duplexes.
Synthetic oligomers that bear no relation to nucleic acids have
also been shown to form duplexes through various non-covalent
interactions: metal–ligand coordination,23,24 salt bridges,25,26
aromatic interactions,27 and hydrogen bonding.28–30 By using
two different complementary recognition sites as the equivalent
of the nucleic acid bases, it is also possible to encode sequence
information into synthetic oligomers, and sequence-selective
duplex formation has been demonstrated for short
sequences.26,31
We have been using a single hydrogen bond between
a hydrogen bond donor (e.g. phenol, D) and a hydrogen bond
acceptor (e.g. phosphine oxide, A) as the base-pairing interac-
tion for duplex formation. This two letter alphabet allows
information to be encoded in an oligomer as the sequence of A
and D recognition sites. Provided the backbone does not
contain any polar functional groups that could compete with
the base-pairing interactions, the use of a single hydrogen bond
as the base-pair removes any possibility of mismatches, because
A cannot interact with A and D cannot interact with D. A
number of different backbone architectures have been
Department of Chemistry, University of Cambridge, Lenseld Road, Cambridge CB2
1EW, UK. E-mail: herchelsmith.orgchem@ch.cam.ac.uk
† Electronic supplementary information (ESI) available: Detailed experimental
procedures with spectroscopic characterization data, 19F NMR titration spectra,
binding isotherms, limiting chemical shis for free and bound states. See DOI:
10.1039/c8sc04896g
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characterized, and the nature of the backbone was found to play
a crucial role in the assembly properties of these oligomers.
The different possible self-assembly channels are illustrated
in Fig. 1. The key requirement for duplex formation is that the
equilibrium constant for propagation of the intramolecular
hydrogen bonds that zip up the duplex, K EMp, is greater than
one (K is the association constant for formation of an inter-
molecular hydrogen bond, and EMp is the effective molarity for
propagation of intramolecular hydrogen bonds in the
duplex).32,33 One of the competing assembly channels is
formation of multiple intermolecular interactions that lead to
higher order networks, but this process can be avoided by
operating at a concentration, c, which is lower than the value of
EMi, the effective molarity for formation of the rst intra-
molecular hydrogen bond that initiates duplex formation. The
other major competing assembly channel is due to the forma-
tion an intramolecular hydrogen bond within an oligomer,
which leads to folding. The probability of this process is
determined by the equilibrium constant K EMf, where EMf is the
effective molarity for folding.
The values of the three effective molarity parameters depend
on the conformational properties of the backbone. For the very
exible backbone shown in Fig. 2(a), the values of EMi and EMp
are 10 mM to 30 mM, and the duplex channel dominates for
length complementary homo-oligomers.34 For the very rigid
backbone shown in Fig. 2(b), similar results were obtained with
EMi and EMp values of 40 mM to 70 mM.35 Geometry is critical
for more rigid backbones. The backbone shown in Fig. 2(b) has
a well-dened geometry, which places the recognition groups in
the correct orientation for duplex formation. However, for
Fig. 2 Backbones (a)–(e) of the previously reported synthetic infor-
mation molecules.34–36,38
backbones of intermediate rigidity, where the conformational backbones (10 mM to 20 mM), but the geometry was not
properties are more difficult to predict, mixed results were ob- compatible with duplex propagation, and EMp was too low to
tained. The backbone shown in Fig. 2(c) formed duplexes with measure.37
EMi ¼ EMp ¼ 10 mM,36 but the backbones shown in Fig. 2(d)
The results obtained for homo-oligomers suggest that highly
and (e) did not lead to extended duplexes. For these two exible backbones should provide a reliable platform for the
systems, EMi was similar to the values found for the other design of duplex-forming oligomers. Conformational exibility
ensures that the backbone will always be able to adapt to
a geometry compatible with base-pair formation in an extended
duplex. More rigid backbones are difficult to design with the
degree of accuracy required to guarantee the geometric
complementarity needed for formation of an extended duplex.37
The values of effective molarity measured for the very exible
backbone and the very rigid backbone shown in Fig. 2 are
similar, so it appears that effective molarities associated with
duplex formation are not adversely affected by conformational
exibility. Very exible backbones are easily accessed, so this
approach would make backbone design straightforward.
However, the effective molarity for intramolecular folding,
EMf, also depends on the conformational properties of the
backbone. As shown in Fig. 3(a), a long exible backbone
promotes 1,2-folding between A and D recognition units that
are adjacent in sequence. The value of EMf for this system is
about 10 mM, which is comparable to the values of effective
molarity for zipping up the duplex, so the folding channel will
dominate for mixed sequence oligomers of this architecture.39
Fig. 1 Possible channels for supramolecular assembly of recognition-
encoded oligomers. The outcome depends on the concentration, c,
the association constant for the intermolecular base-pairing interac-
Of course, longer mixed sequence oligomers will always be able
to fold, no matter what backbone is used, and indeed sequence-
tion, K, and the effective molarities for folding, EMf, duplex initiation,
EMi and duplex propagation, EMp.
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Fig. 3 (a) Intramolecular 1,2-folding in information molecules with
flexible backbones. (b) Duplex formation in information molecules
with rigid backbones.
Fig. 4 (a) Flexible backbones lead to 1,2-folding; (b) rigid backbones
prevent 1,2-folding; (c) recognition units of different dimensions
prevent 1,2-folding; (d) molecular design corresponding to the short-
long base-pairing scheme.
encoded folding of single-stranded RNA is key to the biological
properties.2 Folded nucleic acid structures involve looped out
bases, so if a single-stranded nucleic acid is annealed with
scheme has similar geometrical properties to the purine–
pyrimidine base-pairing system found in nucleic acids.
a
sequence-complementary strand, duplex formation will
dominate, because additional base-pairing interactions are
made in the duplex. However, Fig. 1 shows that if 1,2-folding is
possible, the number of base-pairs formed in the folding and
duplex channels can be identical, so the folding channel will
dominate. Minimising 1,2-folding is therefore critical to the
design of recognition-encoded oligomers that form sequence-
selective duplexes with high delity.
One strategy for avoiding 1,2-folding is to reduce the value of
EMf by increasing the rigidity of the backbone. As shown in
Fig. 3(b), the very rigid backbone that we studied previously
does not fold, so duplex formation is the dominant assembly
channel for mixed sequence oligomers of this architecture.
However, it would be preferable to work with more exible
backbones to guarantee duplex formation, as explained above.
Here, we explore an alternative strategy for preventing 1,2-
folding in oligomers with a very exible backbone. If two short
bases are attached to a long exible backbone, 1,2-folding is
favoured (Fig. 4(a)). Fig. 4(b) illustrates how folding can be
The backbone proposed in Fig. 4(d) uses ester linkages as the
coupling chemistry for the synthesis of oligomers. Esters are
sufficiently weak hydrogen bond acceptors (b z 5.5) not to
compete signicantly with the phosphine oxide recognition
units (b z 10.5).40 Ester coupling is sufficiently high-yielding to
be used for the synthesis of polymers, and iterative coupling
could be automated in a peptide synthesiser.41–43 Orthogonal
protecting groups have been developed for the preparation of
oligoesters with sequences of different building blocks.44–51
Here, we describe synthesis of the required monomer building
blocks, demonstrate their use in the synthesis of different 2-mer
sequences, and show that the long-short base-pairing scheme
successfully prevents 1,2-folding for this oligomer architecture.
2 Results and discussion
2.1 Synthesis
prevented by attaching the two short bases to a rigid backbone. A divergent approach to the synthesis of the monomer building
Fig. 4(c) shows how changing the dimensions of the bases can blocks was employed, in which a common aromatic bromide
be used to prevent folding. By making one of the bases longer intermediate was coupled with the hydrogen bond donor and
than the other, the probability of nding a backbone confor- acceptor recognition units, as shown in Scheme 1. Commer-
mation compatible with folding is signicantly reduced, and cially available 2-bromoethanol 5 was protected as the silyl ether
the duplex assembly channel should dominate. Fig. 4(d) shows 6, which was then used for alkylation of 4-bromoaniline to yield
the corresponding molecular design that we validate in this 7. Aniline 7 was alkylated with benzyl bromoacetate to give the
paper. It is worth noting that this short-long base-pairing key intermediate 8. Commercially available phenol 1 was
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Scheme 1 Synthesis of the orthogonally-protected monomers for information oligoesters.
converted to the boronic ester 2, which was coupled with 8 N,N-dimethylaminopyridine (Scheme 3). Coupling 14 with 15
under Suzuki–Miyaura conditions to give the hydrogen bond gave AA directly. AD and DD were obtained with the phenol
donor monomer 9 (D). Treatment of commercially available groups protected as acetate esters, but these groups were
diethyl phosphite 3 with iso-butylmagnesium chloride gave 4, removed quantitatively by stirring in a solution of ammonium
which was coupled with 8 using palladium(0) and XantPhos to acetate in water and methanol.
yield the hydrogen bond acceptor monomer 10 (A).
For the ester coupling reactions, the potentially reactive
phenol moiety in 9 was rst protected as the acetyl ester 11
(Scheme 2). The benzyl and TBDPS protecting groups in 10 and
11 were removed orthogonally to give the four precursors 12–15
2.2 NMR binding studies
Duplex formation and folding were investigated using 19F and
31P NMR titrations and dilutions in toluene-d8 at 298 K. The
required for ester coupling reactions. Treatment with hydrogen
gas over palladium on charcoal gave the monoprotected
carboxylic acids 12 and 14. Alternatively, reaction with n-tetra-
butylammonium uoride buffered with acetic acid gave the
monoprotected alcohols 13 and 15. These monoprotected
hydroxyacid monomers were used to synthesise three different
2-mer sequences by EDC coupling with a catalytic amount of
Scheme 2 Synthesis of the monoprotected hydroxyacid monomers.
Scheme 3 Synthesis of the AA, DD, and AD 2-mers.
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association constant for formation of the A$D complex, which Therefore, the open complex o-AA$DD has four equally popu-
makes a single intermolecular hydrogen bond, was measured by lated states and the closed duplex c-AA$DD has two.
titrating A into D. A large upeld change in the 19F NMR
It is possible to express the association constants for duplex
chemical shi of D was observed, and the data t well to a 1 : 1 formation in terms of KA$D and EMi:
binding isotherm to give an association constant of KA D ¼ 3.8 ꢀ
1
KAA$DD ¼ 4KA$D
ꢀ
KA$DEMi ¼ 2KA$D2EMi
(1)
103 Mꢁ1 (Table 1). The association constant for the AA$DD
complex was similarly measured by titrating AA into DD, and
the association constant for dimerization of AD was determined
by a 19F NMR dilution experiment in toluene-d8 at 298 K. The
association constants for the AA$DD and AD$AD complexes are
both two orders of magnitude higher than that for A$D, which
indicates that there are two cooperative hydrogen bonding
interactions in the complexes formed by the sequence
complementary 2-mers (Table 1). The limiting 19F and 31P NMR
chemical shis of the free species (dfree) and fully bound
complexes (dbound) were determined by extrapolation of the
binding isotherms (Table 1). The values are similar for all three
complexes. The large upeld limiting complexation-induced
changes in 19F NMR chemical shi (0.4 ppm) indicate that all
of the phenol groups form hydrogen bonds in all of the
complexes. The large downeld limiting complexation-induced
changes in 31P NMR chemical shi (5–7 ppm) indicate that all of
the phosphine oxide groups form hydrogen bonds in all of the
complexes. Comparison of the values of the free 19F and 31P
NMR chemical shis of AA, DD, and AD show that there is no
signicant intramolecular hydrogen bonding in AD, i.e. there is
no folding in the monomeric state. The results indicate that
both the AA$DD and AD$AD duplexes are fully assembled
through the intended base-pairing interactions at mM
concentrations in toluene solution at room temperature as
shown in Fig. 5.
2
Hence the effective molarity for duplex formation can be
determined as:
KAA$DD
2
2KA$D
EMi ¼
(2)
The association constants in Table 1 were used to calculate
EMi for this system as 19 ꢂ 3 mM, which is consistent with
values of supramolecular effective molarities we have measured
for other hydrogen bonded duplexes.31,34–36,38,39 The equilibrium
1
2
constant for closing the duplex is given by KA$DEMi and is 40
for this system, which implies that the duplex is fully closed and
only 2% of the species populate the partially-bound open state
o-AD$AD.
For the closed hetero-2-mer duplex c-AD$AD, there is no
degeneracy associated with the backbone directionality,
because the anti-parallel orientation is determined by the
sequence. However, there is the possibility of intramolecular
1,2-folding in the monomeric state, which is governed by the
corresponding effective molarity EMf. Hence, the observed
dimerisation constant KAD$AD depends on the concentrations of
the folded (ADfolded) and open (ADopen) species that are popu-
lated in the monomeric state:
A schematic representation of the equilibria involved in
duplex assembly is shown in Fig. 6. For AA$DD, formation of the
rst intermolecular hydrogen bond gives an open complex, and
formation of the second intramolecular hydrogen bond gives
the closed duplex. Assuming that all of the hydrogen bonds in
the systems described here are of similar strength, it is possible
to describe the association constant for formation of the closed
c-AA$DD duplex in terms of the association constant for
formation of a single intermolecular hydrogen bond KA$D and
the effective molarity for the intramolecular interaction EMi.
The backbone in these systems has a direction, because the
hydroxyl and acid ends are different, so parallel and anti-
parallel orientations of the duplex are possible. As the end
groups are spatially separated from the recognition sites, we
assume that the two possible c-AA$DD have similar stability.
[AD] ¼ [ADopen] + [ADfold] ¼ [ADopen](1 + KA$DEMf)
(3)
½c-AD$ADꢃ
½c-AD$ADꢃ
KAD$AD
¼
¼
¼
ꢀ
ꢁ ꢂ
ꢃ
2
2
2
½ADꢃ
1 þ KA$DEMf ADopen
KA$D2EMi
(4)
ꢀ
ꢁ
2
2 1 þ KA$DEMf
Assuming that the effective molarity for duplex formation,
EMi, is the same for AA$DD and AD$AD, it is possible to
combine eqn (2) and (4) to determine (KA$DEMf + 1), which is the
factor that describes the fraction of monomeric AD that exists in
the folded state:
rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
KAA$DD
KA$DEMf þ 1 ¼
(5)
4KAD$AD
Table 1 Association constants (K), effective molarities (EM), limiting NMR chemical shifts (dfree and dbound), and complexation-induced changes in
the chemical shifts (Dd) for the formation of duplexes in toluene at 298 K
19F NMR
31P NMR
Complex
log K/Mꢁ1
dfree/ppm
dbound/ppm
Dd/ppm
dfree/ppm
dbound/ppm
Dd/ppm
A$D
AA$DD
AD$AD
3.6 ꢂ 0.1
5.8 ꢂ 0.1
5.2 ꢂ 0.1
ꢁ61.2
ꢁ61.1
ꢁ61.1
ꢁ61.6
ꢁ61.5
ꢁ61.5
ꢁ0.4
ꢁ0.4
ꢁ0.4
34.2
34.3
35.8
41.0
39.3
40.9
6.8
5.0
5.1
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Fig. 5 Hydrogen bonded duplexes formed by (a) the AA and DD 2-mers, and (b) the self-complementary AD 2-mer.
gave the closed c-AD$AD duplex shown in Fig. 7(b) as the lowest
energy structure. No open o-AD$AD structures were found
within 5 kJ molꢁ1 of the minimum. The calculated energy of the
duplex is 87 kJ molꢁ1 lower than the energy of two folded
monomers, which suggests that there is considerable strain
associated with folding in this system.
2.4 Double hydrogen bonding
Oxygen hydrogen bond acceptors can interact with more than
one hydrogen bond donor, which can degrade the delity of
sequence-selective duplex formation.31 In order to investigate
whether the base-pair recognition system used here would
suffer from this problem, A was titrated into DD. The changes in
19F NMR chemical shi of the DD did not t to a 1 : 1 isotherm
(see ESI†), so a 1 : 2 binding model was investigated:
Fig. 6 Competing equilibria in the assembly of (a) the AA$DD duplex
and (b) the AD$AD duplex.
Substituting the values from Table 1 into eqn (5) gives a value
of 1.0 for (KA$DEMf + 1), which is consistent with the NMR
chemical shi data. These results indicate that virtually all
monomeric AD exists in the open state and the 1,2-folding does
not compete with duplex formation in this system.
If the two arrangements of the c-AA$DD were not degenerate,
the statistical factor in eqn (1) would be equal to one, giving
(KA$DEMf + 1) z 1.4. This value would require that 30% of
monomeric AD exists in the folded state, which is not consistent
with the NMR chemical shi data, suggesting that assumption
that the parallel and antiparallel backbone arrangements are
equally populated in the c-AA$DD duplex is reasonable.
K1
DD þ A % DD$A
(6)
(7)
K2
DD$A þ A % DD$A2
The two donor binding sites were assumed to be indepen-
2
dent and identical, hence K1K2 ¼ KA$D could be xed in the
least squares regression analysis. The association constant for
the DD$A was determined to be K1 ¼ (15 000 ꢂ 2000) Mꢁ1
,
which is four times greater than the single hydrogen bond
association constant KA$D and suggests additional stabilisation
2.3 Molecular mechanics calculations
The competition between duplex formation and intramolecular
1,2-folding in AD were further investigated using molecular
mechanics calculations. The OPLS3 force eld with implicit
chloroform solvation model was employed, as implemented in
the MacroModel soware (the experiments were carried out in
toluene, but chloroform is the only non-polar implicit solvent
model implemented).52 A conformational search was performed
on the AD monomer and the lowest energy structure, shown in
Fig. 7(a), is a folded species. The calculation is clearly incon-
sistent with the experimental results, reinforcing our previous
ndings that computational methods do not provide a reliable
method for predicting the self-assembly properties of synthetic
molecules of this complexity.39 To investigate whether this fol-
ded structure is strongly preferred over duplex formation by the
force-eld, two molecules of AD were constrained to have one
Fig. 7 Lowest-energy structures of (a) AD and (b) AD$AD. The OPLS3
force field with implicit chloroform solvation model was employed.
Protecting groups and alkyl groups on phosphorus were replaced with
methyl groups. Carbon atoms are colour coded by molecule, and
hydrogen atoms are not shown for clarity. Hydrogen bonds are shown
intermolecular hydrogen bond, and a conformational search as dotted lines.
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due to a hydrogen bond between the second phenol and the recognition units should lead to superior performance the
phosphine oxide. We can represent the equilibria leading to the formation of closed duplexes with high sequence delity.
doubly bonded complex as in Fig. 8.
Noting that both 1 : 1 complexes give rise to the observed
association constant, K1 can be expressed as:
3 Conclusions
In conclusion, candidates for new information molecules were
K1 ¼ 2KA$D + 2KA$DK0
(8)
synthesised and their behaviour in toluene was studied through
19F and 31P NMR spectroscopy. The monomeric building blocks
are readily accessible and 2-mers were easily synthesised
through efficient ester coupling reactions, with scope for the
synthesis of longer oligomers using the same methodology. A
long-short base-pairing scheme akin to purines and pyrimi-
dines in natural nucleic acids was employed in order to reduce
intramolecular folding and a exible backbone was used to
ensure the geometric complementarity required for duplex
formation. Homo- and hetero-2-mers were observed to form
stable duplexes in toluene at 298 K with effective molarities for
duplex formation of 20 mM and without any substantial 1,2-
folding. The observed trends were consistent with those previ-
ously reported using 31P NMR, thus providing a convenient
handle for studying supramolecular association. Formation of
double hydrogen bonds to the oxygen-based acceptor was found
to be much less favoured than the desired base-pairing inter-
actions. This system appears to be ideally suited to the synthesis
of longer oligomers which are expected to show the possibility
of high-delity sequence-specic information recognition via
hydrogen bonding in organic solvents.
The association constant for the formation of the second
hydrogen bond is, therefore:
K1 ꢁ 2KA$D
2KA$D
K1
K0 ¼
¼
ꢁ 1
(9)
2KA$D
Using eqn (9) and the measured value for K1, the association
constant for the interaction of the second phenol donor with
the acceptor is K0 (1.0 ꢂ 0.2), which means that the double-
bonded complex represents 50% of the 1 : 1 complex. The
ratio of KA$DEMi and K0 describes the competition between
a correctly recognised duplex and a doubly hydrogen-bonded
mismatched complex. This ratio is 80 for this system, there-
fore sequence selectivity should be achieved for longer infor-
mation oligoesters with delity of 99%. For comparison, the
previously reported sequence-containing information oligomer
shows K0 ¼ 1.6 and KA$DEMi ¼ 9.9, hence exhibits sequence
delity of 86%.31,39 While the value of K0 for the system
described here is comparable with that reported earlier, the
exceptionally strong hydrogen-bonding interaction between the
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank the European Research Council (ERC-2012-AdG
320539-DUPLEX) for funding.
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