Rationally designed cooperatively enhanced receptors to magnify host-guest binding in water

Article abstract of DOI:10.1021/ja510823h

When disengaged interactions within a receptor are turned on by its guest, these intrahost interactions will contribute to the overall binding energy. Although such receptors are common in biology, their synthetic mimics are rare and difficult to design. By engineering conflictory requirements between intrareceptor electrostatic and hydrophobic interactions, we enabled complementary guests to eliminate the "electrostatic frustration" within the host and turn on the intrahost interactions. The result was a binding constant of K_a >10⁵ M^-1 from ammonium-carboxylate salt bridges that typically function poorly in water. These cooperatively enhanced receptors displayed excellent selectivity in binding, despite a large degree of conformational flexibility in the structure.

Full text of DOI:10.1021/ja510823h

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Article
Rationally Designed Cooperatively Enhanced
Receptors to Magni-fy Host–Guest Binding in Water
Roshan W. Gunasekara, and Yan Zhao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja510823h • Publication Date (Web): 22 Dec 2014
Downloaded from http://pubs.acs.org on December 29, 2014
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Rationally Designed Cooperatively Enhanced Receptors to Magnify
Host–Guest Binding in Water
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Roshan W. Gunasekara and Yan Zhao*
Department of Chemistry, Iowa State University, Ames, Iowa 50011-3111
Supporting Information Placeholder
effective strategies to overcome the problem of negative con-
formational entropy when they tighten up in the presence of
their guests.
ABSTRACT: When disengaged interactions within a recep-
tor are turned on by its guest, these intrahost interactions will
contribute to the overall binding energy. Although such re-
ceptors are common in biology, their synthetic mimics are
rare and difficult to design. By engineering conflictory re-
quirements between intrareceptor electrostatic and hydro-
phobic interactions, we enabled complementary guests to
eliminate the “electrostatic frustration” within the host and
turn on the intrahost interactions. The result was a binding
29
After studying protein and other naturally occurring recep-
tors, Williams and co-workers proposed an interesting pos-
tulation that the driving force for guest-binding does not all
have to come from direct host–guest interactions but may de-
rive from cooperative strengthening of existing interactions
2
3
within the host. Essentially, binding in bioreceptors can be
delocalized over the entire structure, not confined at the
host–guest interface.
5
-1
a
constant of K >10 M from ammonium–carboxylate salt
bridges that typically function poorly in water. These cooper-
atively enhanced receptors displayed excellent selectivity in
binding, despite a large degree of conformational flexibility
in the structure.
Delocalized binding in cooperatively enhanced receptors
(
CERs) has indeed been realized in several synthetic recep-
tors. Kubik, Otto, and co-workers prepared a peptidic
bismacrocyclic anion receptor whose hydrophobic interac-
tions between the two macrocycles assisted the anion bind-
30
ing. Carrillo et al. reported a crown ether-like macrocycle in
which a remote intrahost hydrogen bond strengthened the
binding of aromatic amino acid ester in an enantioselective
Introduction
Biological hosts have extraordinary abilities to recognize
and bind guests in competitive aqueous environments, even
well solvated hydrophilic small molecules whose binding is
not expected to gain much binding enthalpy. A survey of bio-
logical and synthetic host–guest complexes by Houk et al.
over a decade ago revealed a large gap between the two
groups of receptors: whereas nanomolar or stronger affinities
are frequently seen in the former, millimolar affinities repre-
2
7
fashion. Our group reported an oligocholate foldamer host
that exhibited strong cooperativity between the host confor-
mation and guest binding, with the strongest binding occur-
31
ring at the folding–unfolding transition.
CERs essentially utilize the positive cooperativity between
intrahost interactions and (direct) host–guest interactions to
reinforce their guest-binding. An exciting implication of such
receptors is that high binding affinity can be obtained even
from weak (direct) binding forces, as long as sufficient in-
trahost interactions can be triggered by the guest. Unfortu-
nately, despite the attractiveness and huge potential of such
receptors, their rational design represents a formidable task.
While preorganization gives chemists a clear path to follow
in designing guest-complementary receptors, cooperative
enhancement seems more of a rationale for existing phenom-
ena as it stands. Even for the above mentioned synthetic
CERs, their discovery appeared to be by accident rather than
by design.
1
sent the average for the latter. Chemists indeed developed
2
-4
extremely tight binders in isolated cases; such, nonethe-
less, remain as rare exceptions to the norm in synthetic su-
pramolecular chemistry.
Interestingly, evident from the large number of tight-bind-
ing drugs developed for bioreceptors, there seems to be no
fundamental deficiency in chemists’ ability to construct tight-
binding guests for biological hosts. If this is indeed the case,
the “deficiency” of synthetic host–guest complexes likely lies
in the receptors that admittedly are less complex and smaller
in size in comparison to common biological hosts.
The majority of synthetic receptors have been created us-
In this paper, we report a rational design of CERs that op-
erate in aqueous solution. Weak ammonium–carboxylate
salt bridges were enhanced by hydrophobic interactions
within the receptor to afford strong binding in water. The key
design of the system centers on the “electrostatically frus-
trated” intrahost interactions that could be strengthened by
a suitable guest. Not only strong binding was obtained in wa-
ter from relatively weak binding forces, excellent selectivity
was also achieved for a highly flexible receptor.
5
,6
ing the concept of preorganization. The concept played vi-
tal roles in the development of supramolecular chemistry in
7-22
the last decades.
More recently, however, an increasing
number of chemists began to wonder whether alternative
23-28
strategies exist in constructing tight-binding receptors.
Since bioreceptors are often made of flexible peptide chains
with rich conformational dynamics even in the folded state,
it seems flexibility cannot be inherently detrimental to high
binding affinity. Not only so, flexible bioreceptors must have
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Results and Discussion
glutamic acid tether to facilitate the choate–cholate interac-
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6
tion. Our previous work shows that a C4 tether in between
two cholates allows the facial amphiphiles to interact with
Design of CERs. As shown by Scheme 1, our CER con-
sists of a central scaffold (S) to which two insulated “folding
arms” are attached. Each arm can fold upon itself by the in-
trahost A–A′ interactions. The two binding functionalities
35
each other fairly easily. In Scheme 2, the terminal carbox-
ylate (highlighted by the red circle) corresponds to the bind-
ing functionality B in Scheme 1 and the two cholates are es-
sentially A and A′, respectively.
(B) are designed to be far apart in the unfolded CER but in
proximity in the folded conformer. As a result, the electro-
static interactions between the two negatively charged B’s are
in conflict with the A–A′ interactions in the folded conformer
and thus interfere with the folding. When a suitable, oppo-
sitely charged guest (G) binds, it engages direct electrostatic
host–guest interactions and, more importantly, by neutraliz-
ing the electrostatically repelled B’s, strengthens the in-
trahost A–A′ interactions. In this way, the formerly “frus-
trated” intrareceptor hydrophobic interactions are “turned
on” by the guest and will contribute to the binding energeti-
cally. As will be shown by our study, the CER does not have
to be fully unfolded prior to binding to be operative. As long
as the intrahost A–A′ interactions are not fully engaged be-
fore the CER binds the guest, they could contribute to the
binding. Similar to biological CERs, the system has the “bind-
ing interactions” delocalized over much of the entire struc-
ture, with remote A–A′ interactions being utilized to magnify
the direct binding forces at the B–G–B interface.
The synthesis of 1 followed standard chemistry employed
32
in other oligocholate synthesis and can be found in the Sup-
porting Information. Our synthesis left an azido group on the
cholate, which made it convenient to label the arm with an
environmentally sensitive fluorophore (2) using click chem-
istry.
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Scheme 2. Idealized folding of bischolate foldamer 1 in
polar and nonpolar solvents.
Figure 1 shows the maximum emission intensity of com-
pounds 1 () and 2 () in two solvent mixtures. The inten-
sity of each compound was normalized to the emission of the
same compound in methanol so that the two compounds can
be better compared. The x-axes are drawn such that the sol-
vent polarity increases continuously from left to right all the
way across Figure 1a,b.
Scheme 1. Design of an electrostatically frustrated CER
and its binding of an oppositely charged ligand to trigger
intrahost A–A′ interactions.
Notably, the CER is highly flexible by design. The guest-
induced conformational change is strategically utilized in-
stead of being avoided as in typical preorganized systems.
Yet, because the optimal guest needs to match the B–B dis-
tance in the folded CER both electrostatically and geometri-
cally, a strong binding selectivity may still be possible despite
the flexibility.
Synthesis and Conformational Study. To realize the
above design, we first synthesized bischolate 1 as the folding
arm, with a fluorescent label to study its folding/unfolding
(
Scheme 2). Our group has a long interest in cholate folda-
Figure 1. Maximum emission intensity of bischolate 1 ()
and control compound 2 () normalized to the intensity of
the same compound in methanol as a function of solvent
composition in (a) THF/methanol and (b) water/methanol
mixtures. The data points are connected by colored lines to
guide the eye. λex = 340 nm. [Compound] = 2.0 μM.
mers except that the earlier examples had their monomers
joined by amide groups on the hydrophilic α-face of the cho-
32-34
late.
Because the two cholates in 1 need to interact
through hydrophobic interactions of the β-faces in water, we
connected the cholates by the β-amino group, with a flexible
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According to Figure 1, the two compounds responded to
solvent polarity similarly at intermediate polarity, evident
from the nearly overlapping I/I curves in between 30%
THF/methanol and 50% methanol/water (indicated by the
green arrow). However, the curves deviated from each other
when the solvents became either more polar or less polar. Im-
2 in Figure 1b. Intermolecular aggregation was ruled out by
1
2
3
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7
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5
6
dilution studies. More importantly, the fluorescence in >50%
water/methanol displayed a sigmoidal transition, a hallmark
0
39,40
of cooperative conformational change.
The data fit al-
most perfectly to a two-state unfolding–folding transition
4
1
model (Figure 2b) that is characteristic of many proteins
and solvophobic foldamers,
32,42
portantly, as the I/I
0
curves moved apart, 1 () had stronger
suggesting that the proposed
(
normalized) emission than 2 () toward the polar end but
cooperative folding indeed was operating.
weaker emission toward the nonpolar end.
The aminonaphthalene sulfonate in 1 and 2 is an analogue
of the more common fluorophore dansyl, which emits
strongly in nonpolar environments and weakly in polar
(
a)
2
(b)
.5
.0
.5
.0
0
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36
ones. Since a similar effect was operating in 2, the stronger-
than-usual emission of 1 in the most polar solvents suggests
that its fluorophore has a higher environmental hydrophobi-
city than 2 in the most polar solvents, and vice versa in the
most nonpolar solvents. This kind of crossing-over in solvent
response was identical to what was observed in our cholate-
based molecular baskets, which adopted a micelle-like con-
formation (with exposed hydrophilic faces) in polar solvents
2
1
1
I/I0
fU
0
20
40
60
80
100
30
50
70
90
% Water in MeOH
% Water in MeOH
and reverse-micelle-like conformation (with buried hydro-
philic faces) in nonpolar solvents.3
7,38
Conceivably, as 1
Figure 2. (a) Maximum emission intensity of “3-armed” 3
() and control compound 4 () normalized to the intensity
of the same compound in methanol as a function of solvent
composition. λex = 240 nm. [Compound] = 2.0 μM. (b) Non-
linear least squares curve fitting of the fluorescence data of 3
in ≥40% water/methanol to a two-state transition model,
showing the fraction of unfolded conformer as a function of
solvent composition.
folded in polar solvents via the hydrophobic cholate–cholate
interactions (Scheme 2), the fluorophore was sensing the hy-
drophobic local environment and thus emitted more strongly
than the control compound. When 1 folded in nonpolar sol-
vents (in THF with low methanol), the hydrophilic faces
turned inward, with the many polar groups toward the center
of the molecule concentrating methanol near the fluoro-
phore—this type of solvent-induced conformational change
has been observed multiple times for both cholate folda-
32,38
37,38
mers
and nonfoldamers
under similar conditions.
Taken together, it seems that the bischolate arms could
fold hydrophobically in >50% water/methanol. The similar
response of the 1-armed and 3-armed compounds toward
solvent polarity suggests that these arms folded inde-
pendently. The more important questions, however, were
whether these arms indeed could enhance the binding of 3 as
a receptor and which factors would control the cooperative
enhancement.
Since the bischolate arm seemed to operate as intended, we
prepared CER 3 by clicking three such arms (5) to 1,3,5-tri-
ethynylbenzene. A control compound 4 was similarly pre-
pared to help us understand the conformation of 3. We chose
the rigid trisubstituted benzene as the central scaffold so that
the bischolate arms are separated or “insulated” from one an-
other. Clearly, we did not want cholate–cholate interactions
to occur across different arms.
Guest-Binding of the CERs. To evaluate the molecular
recognition of 3, we synthesized a hexacarboxylated ana-
logue 6 as a control receptor, which lacks the key cooperative
conformational change of 3. Its three ortho carboxylates
mimic the three terminal carboxylates from the cholates that
are responsible for binding triammonium guests such as 7.
Its para carboxylates mimic the three glutamate carboxylates
in the midsection of 3 to provide solubility in aqueous solu-
tion. Keeping the compounds charged is important to water-
solubility of the host–guest complex, especially when the am-
monium guest neutralizes the cholate or the ortho carbox-
ylates in 3 and 6, respectively.
0
Figure 2a shows the I/I curves of 3 and 4. We focused on
the polar side of the solvent scale (i.e., methanol/water mix-
tures), as the receptor was designed to function in water
through the hydrophobic interactions of the β-cholates. Re-
markably, the curves for 3 and 4 once again nearly over-
lapped in <50% water/methanol but moved apart as the sol-
vent became more polar, similar to what happened to 1 and
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cussed later) was 1.1 ± 0.2 according to the ITC titrations, in-
dicating that 1:1 binding stoichiometry was indeed in opera-
tion as designed.
1
The binding of the two receptors was studied by isothermal
titration calorimetry (ITC). ITC is often the method of choice
for binding studies. Not only could one determine binding
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The binding data so far are consistent with the designed
cooperatively enhanced binding. Not only was the flexible
CER able to bind more strongly than the more “preor-
ganized” control receptor 6 with the same number of salt
a
constants (K ) in a broad range, other important parameters
including the binding enthalpy, entropy, and the number of
binding sites (N) on the receptor could all be obtained simul-
taneously.
43
bridges, the two bindings had opposite driving forces. The
entropically driven binding of 3 also strongly supports our
CER design: since the intrahost hydrophobic interactions
were expected to contribute to the binding and a large num-
ber of water molecules will be released to the bulk solution
during hydrophobic association of the cholates, a strong en-
tropic driving force is anticipated. According to Figure 2b, 3
was fully folded in 100% water. Since the folding was hydro-
phobically driven, the cholate–cholate hydrophobic interac-
tions must have been already engaged to a large degree prior
to binding. The fact that additional hydrophobic driving force
could be “transferred” to the guest-binding suggests that the
cholates were not tightly packed in folded 3 prior to the bind-
ing, as expected from the proposed repulsion between the
terminal carboxylates.
Both receptors (3 and 6) relied on the three introverted
carboxylates for binding; the difference between the two was
in how the carboxylates were folded back—by conformational
changes and a rigid covalent framework, respectively—and
whether cooperative conformational change was involved in
the binding. As shown by Figure 3, the titration data for both
compounds fit nicely to a 1:1 binding model but the two bind-
ings had completely opposite heat of reaction, with 3 show-
ing a positive/unfavorable enthalpy and 6 a large nega-
tive/favorable enthalpy.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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7
8
9
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2
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6
7
8
9
0
Table 1. Binding data obtained by ITCa
K
a
ΔG
ΔH
TΔS
Entry Complex
3
-1
(
10 M ) (kcal/mol) (kcal/mol) (kcal/mol)
1
2
3
4
5
6
7
8
9
3·7
3·7b
3·7c
3·7d
3·8
138 ± 2
49 ± 9
-7.0
-6.4
-5.2
-5.8
-5.5
10.5
71.0
114.0
-1.6
17.5
77.4
119.2
4.2
6.8 ± 0.2
19 ± 1.6
11 ± 6
35.4
40.9
3·9
3·10e
8.0 ± 1.0
--
-5.3
--
-1.7
--
3.6
--
3·11
23 ± 1
24 ± 10
--
-5.9
2.8
8.7
6·7
6·8e
-6.0
--
-35.6
--
-29.6
--
Figure 3. ITC titration curves obtained at 298 K for the
binding of 7 by (a) 3 and (b) 6. The data correspond to entries
1
0
6·9e
--
--
--
--
1
and 9 in Table 1. In a typical experiment, a 2–6 mΜ aqueous
11
solution of the guest in Millipore water was injected in equal
steps of 10.0 μL into 1.42 mL of 0.05–0.2 mΜ solution of the
host in Millipore water. The top panel shows the raw calori-
metric data. The area under each peak represents the amount
of heat generated at each ejection and is plotted against the
molar ratio of the guest to the host. The smooth solid line is
the best fit of the experimental data to the sequential binding
of N equal and independent binding sites on the MINP. The
heat of dilution for the guest, obtained by adding the guest to
Millipore water, was subtracted from the heat released dur-
ing the binding. Binding parameters were auto-generated af-
ter curve fitting using Microcal Origin 7.
12
12·13
12·14
2.2 ± 0.5
150 ± 30
-4.6
-7.1
9.9
14.5
-1.3
13
-8.3
a
The titrations were generally performed in duplicates in water and the
errors between the runs were generally <10%. The number of independ-
b
ent binding sites (N) was found to be 1.1 ± 0.2. The binding was deter-
c
mined in a 80:20 water/methanol mixture. The binding was determined
d
in a 60:40 water/methanol mixture. The binding was determined in PBS
buffer (pH 7.4, 137 mM NaCl, 2.7 mM KCl). e The binding was too weak
to be determined by ITC.
The formation of 6·7 was enthalpically driven (Table 1, en-
try 9). The binding affinity for triammonim 7 by 6 in water
was ~6 times stronger than that by a triphosphonate receptor
3
-1
44
a 2
(K = 4 × 10 M in D O) in the literature for the same guest.
The stronger binding by 6 likely comes from the secondary
electrostatic interactions between the ammoniums on the
guest and the para carboxylates of 6. The enthalpic driving
force seems reasonable. Although ionic interactions have
The thermodynamic parameters for the bindings are sum-
marized in Table 1. Entries 1 and 9 show that the flexible CER
(
a
3) was able to bind triammonium 7 in water with a K of 138
3
-1
× 10 M , ca. 6 times stronger than that of the more rigid con-
trol receptor (6). The difference corresponds to 1 kcal/mol
binding free energy (ΔG). Formation of 3·7 was entropically
driven, with a positive/favorable binding entropy (TΔS = 17.5
kcal/mol) that more than compensated the unfavorable
binding enthalpy of ΔH = 10.5 kcal/mol. In contrast, the rigid
receptor 6 has a large favorable enthalpy (ΔH = -35.6
kcal/mol) that was offset by an also large entropic term (TΔS
= -29.6 kcal/mol). To our delight, the number of independent
binding sites (N) for all the receptors (3, 6, and 12 to be dis-
45-48
been reported to afford positive entropy in some cases,
it
is also well known that strong ionic interactions have favora-
47,49
ble enthalpic contribution.
In the case of 6, any favorable
entropy obtained through release of water molecules during
desolvation was probably overcome by increased order of the
complex. One source for the higher order could come from
the loss of conformational freedom in the receptor during
binding. The free receptor is unlikely to have all the carbox-
ylates on the same side of the molecule, due to electrostatic
repulsion of the ortho carboxylates and multiple rotatable
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bonds in the 1,3,5-tris(triazolyl)benzene scaffold. Binding be-
tween 6 and 7 would undoubtedly freeze the conformation of
the host, leading to a reduction of entropy.
7.1 kcal/mol for 12·14 in water (Table 1, entry 13). As shown
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
3
3
3
3
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6
by Figure 4, the ITC curves for 13 and 14 once again dis-
played different types of driving forces, with the binding of
diammonium 13 endothermic and the binding of diguani-
dinium 14 exothermic. If we assume the intrahost cholate–
cholate interactions are hydrophobic and entropic in origin,
the switching from entropy- to enthalpy-driven binding from
The intrahost hydrophobic contribution to the formation
of 3·7 was additionally confirmed by the addition of metha-
nol to the aqueous solution. As shown by entries 2 and 3 of
Table 1, the binding affinity continued to decline with in-
creasing amounts of methanol. Additionally, in PBS buffer,
which contained significant amounts of electrolytes (NaCl,
KCl, and sodium phosphate), the binding was also weakened
significantly (entry 4). The result is consistent with our pro-
posed binding mechanism. As the electrolytes lowered the re-
pulsion among the negatively charged carboxylates in the
folded CER, the intrahost cholate–cholate hydrophobic in-
teractions become more fully engaged prior to the guest
binding, destroying the very basis of the cooperative en-
hancement. These results are also in agreement with our ear-
lier conclusion that, even though 3 was fully folded (Figure
1
3 to 14 could suggest that cooperative enhancement by the
intrahost interactions is more important to a receptor whose
direct host–guest binding forces are weaker. Stated differ-
ently, the stronger the direct binding forces, the less the bind-
ing needs to rely on intrahost interactions to afford high
binding affinity. Many bis- and tris-guanidinium–carbox-
ylate host–guest complexes have been reported in the litera-
0
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46,50-52
ture,
they often did not function in pure aqueous solu-
tion or displayed much weaker binding than what was ob-
served for 12·14. The enhanced binding in the CER suggests
that cooperative hydrophobic intrahost interactions could in-
deed magnify polar interactions that are compromised by
water.
2
b), the cholates were not tightly packed due to the repulsion
among the cholate carboxylates.
Our CER model in Scheme 1 predicts selectivity in the
binding, as the optimal guest needs to fit in between the bind-
ing groups in the folded CER. The prediction was confirmed
in the bindings of guests 8–11. The addition of a single meth-
ylene spacer (8 vs. 7) lowered the binding affinity (of 8) by
an order of magnitude. Compound 9 differs from 8 by an-
other oxygen spacer; its binding by 3 was similarly weak.
Thus, despite the tremendous flexibility of the conformation-
ally mobile CER, not only could it bind its guest tightly in wa-
ter, it also did so with quite impressive selectivity.
Somewhat surprisingly, 3 had no detectable binding for
the ammonium salt of TREN (10). It is unclear to us why this
compound could not bind, given its similarity to 7 in size and
the terminal amine groups. On the other hand, it is interest-
ing to note that diammonium salt 11 was bound with quite a
remarkable affinity in water. Even though its binding con-
stant was weaker than that for 7 (as expected), a K
a
of 23 ×
3
-1
10 M was 2–3 times higher than the “slightly-mismatched”
triammonium 8 and 9. We believe this result actually derived
from our CER binding mechanism. Although three ammoni-
ums are optimal for binding CER 3, two such groups are suf-
ficient to “disarm” the electrostatically frustrated bischolates.
This is because when two salt bridges are formed between 3
and 11, the third cholate carboxylate would not face signifi-
cant repulsion in the guest-binding folded state. As a result,
even when the third salt bridge was absent, all the other in-
trahost hydrophobic interactions among the cholates could
be turned on by 11 to enhance its binding.
Figure 4. ITC titration curves obtained at 298 K for the
binding of (a) 13 and (b) 14 by 12. The data correspond to
entries 12 and 13 in Table 1.
If the folding arms are essential to the CER, reducing its
number should weaken the binding dramatically. To verify
this hypothesis, we synthesized 2-armed CER 12 and studied
its binding of diammonium 13 and diguanidinium 14. As
predicted, the 2-armed receptor displayed weaker binding
Conclusions
3
-1
The significance of this work lies in the rational design of
cooperatively enhanced receptors (CERs) that employ “hid-
den” intrahost interactions to magnify weak polar binding
forces. Our strategy makes the binding delocalized over the
entire structure of the receptor instead of being confined at
the binding interface. This type of receptors essentially ex-
ploit the positive cooperativity between the guest-binding
for diammonium 13, with a K
a
of 2.2 × 10 M (Table 1, entry
12) or about 60 times weaker than that of 3·7. It is worth not-
ing that, although two salt bridges are formed in both 3·11
and 12·13, the former complex was 10 times more stable than
the latter. The result once again confirms that the intrahost
cholate–cholate interactions were critical to the binding.
Since three such interactions can be formed in 3·11 but only
two in 12·13, the higher stability of the former is anticipated,
despite the same number of salt bridges formed in both com-
plexes.
5
3
and intrahost interactions to augment each other. Despite
the flexibility of the receptor, high binding selectivity is still
possible, even though the selection rule is quite different
from what governs a preorganized receptor: instead of fitting
snuggly into a rigid pocket, the best guest needs to turn on
the most number of non-engaged intrahost interactions prior
to binding.
A stronger direct binding force between the carboxylate
and guanidinium not surprisingly enhanced the binding even
3
-1
a
further, giving an impressive K of 150 × 10 M with ΔG = -
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There is strong support for Williams’s postulation of delo-
calized, cooperatively enhanced binding in biology. When
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streptavidin binds biotin, the melting point of the protein
host increases by 37 °C and numerous backbone amide pro-
2
3
tons become resistant to H/D exchange. In contrast to hun-
dreds or thousands preorganized synthetic receptors already
synthesized, very few CERs have been made by chemists.
Hopefully, the rational design of CERs will accelerate the de-
velopment of these biomimetic receptors and help chemists
create ultrastable host–guest complexes even when strong
direct host–guest interactions are unavailable—this could be
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tainly is not the only strategy for CERs and additional designs
will emerge for sure as more researchers join this pursuit.
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27,28,30,31
receptors. All the previous CERs
and the ones re-
ported in this study all have a significant degree of preorgan-
ization, in the sense that some rigid scaffolds are used in the
construction of the receptor to avoid total flexibility, which
could be detrimental to both binding affinity and selectivity.
A fine balance of the two strategies will most likely be needed
for optimal complexes, as nature has amply demonstrated.
(
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ASSOCIATED CONTENT
Supporting Information
Experimental details for the syntheses and additional figures.
This information is available free of charge via the Internet at
http://pubs.acs.org.
(
(
(
AUTHOR INFORMATION
Corresponding Author
zhaoy@iastate.edu
(31) Zhong, Z.; Li, X.; Zhao, Y. J. Am. Chem. Soc. 2011, 133, 8862-
8865.
(
(
32) Zhao, Y.; Zhong, Z. J. Am. Chem. Soc. 2005, 127, 17894-17901.
33) Cho, H.; Zhao, Y. J. Am. Chem. Soc. 2010, 132, 9890-9899.
(34) Zhao, Y.; Cho, H.; Widanapathirana, L.; Zhang, S. Acc. Chem.
Res. 2013, 46, 2763-2772.
Notes
The authors declare no competing financial interests.
(35) Zhao, Y. J. Org. Chem. 2009, 74, 834-843.
(
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37) Ryu, E.-H.; Yan, J.; Zhong, Z.; Zhao, Y. J. Org. Chem. 2006, 71,
7205-7213.
ACKNOWLEDGMENT
We thank NSF (CHE-1303764) for financial support of the
research.
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ammoniums and the more distant carboxylates in 3 and 6, are
considered, 6 should be favored over 3 because its para
carboxylates are closer to ammoniums on the guest than the
glutamate carboxylates in 3.
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to enhance its binding of oppositely charged species. For exam-
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53) Micelles of ionic surfactants are also known to be electrostati-
cally frustrated and the electrostatic frustration has been shown
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