Self-Assembled Multivalent Ag-SR Coordination Polymers with Phosphatase-Like Activity

Article abstract of DOI:10.1002/chem.202100368

We show herein the phosphatase-like catalytic activity of coordination polymers obtained after adding Ag⁺-ions to thiols bearing hydrophobic alkyl chains terminated with a 1,4,7-triazacyclononane (TACN) group. The subsequent addition of Zn²⁺ -ions to the self-assembled polymers resulted in the formation of multivalent metal coordination polymers capable of catalysing the transphosphorylation of an RNA-model compound (2-hydroxypropyl-4-nitrophenyl phosphate, HPNPP) with high reactivity. Analysis of a series of metal ions showed that the highest catalytic activity was obtained when Ag⁺-ions were used as the first metal ions to construct the backbone of the coordination polymer through interaction with the -SH group followed by Zn²⁺-ions as the second metal ions complexed by the TACN-macrocycle. Furthermore, it was demonstrated that the catalytic activity could be modulated by changing the length of the hydrophobic alkyl chain.

Full text of DOI:10.1002/chem.202100368

Communication
doi.org/10.1002/chem.202100368
Chemistry—A European Journal
Self-Assembled Multivalent Ag-SR Coordination Polymers
with Phosphatase-Like Activity
Ying-Juan Cao+,[a] Mei-Xia Yao+,[a] Leonard J. Prins,[b] Rui-Xue Ji,[a] Ning Liu,[a]
Xiang-Ying Sun,[a] Yun-Bao Jiang,*[c] and Jiang-Shan Shen*[a]
process and the enzyme structure is generally easily disrupted
by environmental conditions, such as temperature, pH, salt
Abstract: We show herein the phosphatase-like catalytic
activity of coordination polymers obtained after adding
concentration, and organic solvents. This limits a practical
Ag+-ions to thiols bearing hydrophobic alkyl chains termi-
application of enzymes in chemo- or biosensing,[3] because of
nated with a 1,4,7-triazacyclononane (TACN) group. The
an incompatibility with the requested reaction conditions.
subsequent addition of Zn2+ -ions to the self-assembled
Artificial enzymes, in particular nanozymes, are rapidly gaining
polymers resulted in the formation of multivalent metal
interest as robust synthetic analogs of enzymes.[4] These artificial
coordination polymers capable of catalysing the trans-
enzymes are expected to overcome the operational limitations
phosphorylation of an RNA-model compound (2-hydroxy-
of natural enzymes, while maintaining an acceptable catalytic
propyl-4-nitrophenyl phosphate, HPNPP) with high reactiv-
activity. In fact, numerous artificial enzymes for a wide variety of
ity. Analysis of a series of metal ions showed that the
chemical reactions have been developed over the past two
highest catalytic activity was obtained when Ag+-ions were
decades.[5] One class of nanozymes that has received prominent
used as the first metal ions to construct the backbone of
attention are artificial phosphatases used for the transphos-
the coordination polymer through interaction with the -SH
phorylation of phosphodiesters.[6–9] The design of these nano-
group followed by Zn2+-ions as the second metal ions
zymes typically relied on the incorporation of multiple copies of
complexed by the TACN-macrocycle. Furthermore, it was
1,4,7-triazacyclononane·Zn2+ (TACN·Zn2+) complexes in a wide
demonstrated that the catalytic activity could be modulated
variety of structures ranging from simple molecules,[6] to multi-
by changing the length of the hydrophobic alkyl chain.
valent systems, like micelles,[7] vesicles,[8] and dendrimers (Fig-
ure 1).[9] A key feature of the catalysis is its cooperative nature,
implying that (at least) two TACN·Zn2+ complexes are required
in the active site. Although multivalent structures showed
The ability of enzymes to accelerate chemical reactions is of
utmost importance to living systems.[1] Selectivity in substrate
recognition allows enzymes to carry out their specific task in
the complex intracellular environment. The unrivalled catalytic
activity of proteases originates from the spontaneous folding of
the peptide chains in an ingenious tertiary structure in which
the remote catalytic sites are brought into close proximity in
the active pocket.[2] However, the protein folding is a delicate
impressive properties owing to the installment of cooperative
effects between neighboring (TACN·Zn2+) complexes, for prac-
tical applications the low stability of amphiphile-based assem-
blies (as pointed out by Scrimin et al.)[10] and the synthetic
accessibility of dendrimers pose limitations.[11] These limitations
have been overcome using gold nanoparticles as inorganic
scaffold for the immobilization of a monolayer of alkyl thiols
terminating with TACN·Zn2+ complexes. Formation of the
monolayer occurs through a self-assembly process and the
strength of the AuÀ S bond confers a high stability to the
resulting structure. Compared to the other classes, these
monolayer protected gold nanoparticles were shown to have
[a] Y.-J. Cao,+ M.-X. Yao,+ R.-X. Ji, N. Liu, Prof. X.-Y. Sun, Prof. J.-S. Shen
Xiamen Key Laboratory of Optoelectronic Materials and Advanced
Manufacturing, College of Materials Science and Engineering,
Huaqiao University
superior
catalytic
properties
in
the
cleavage
of
phosphodiesters.[10a,12] Nonetheless, the synthesis of the mono-
layer protected Au nanoparticles is a multistep procedure and
the purification requires size-exclusion chromatography. Here,
we demonstrate a new class of multivalent coordination
polymeric systems with excellent catalytic activity as trans-
phosphorylation catalysts that can be prepared using facile
procedures and does not require any kind of purification.
In recent years, coordination polymers based on Ag-SR
interactions have been studied by us and others.[13] These metal
coordination polymers could be obtained in situ by simply
mixing Ag+-ions and thiols. Stimulated by these findings, we
decided to study whether the in situ formation of metal
coordination polymers upon mixing equal amounts of Ag+-ions
Xiamen, 361021, China
E-mail: jsshen@hqu.edu.cn
[b] Prof. L. J. Prins
Department of Chemical Sciences
University of Padova
Via Marzolo 1, 35131 Padova, Italy
[c] Prof. Y.-B. Jiang
Department of Chemistry, College of Chemistry and Chemical Engineering,
MOE Key Laboratory of Spectrochemical Analysis,
Xiamen University
Xiamen 361005, China
E-mail: ybjiang@xmu.edu.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202100368
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Figure 1. Schematic comparison of previously reported artificial phosphatases (a), and in situ formation of metal coordination polymers by using HS-Cn-TACN
with various lengths of alkyl chain (n=5-20), and catalytic cleavage reaction of these systems in this work (b).
and alkyl thiols containing a TACN-moiety would be a viable
method to obtain multivalent systems with catalytic activity in
transphosphorylation reactions (Figure 1). In these systems, Ag+
-ions would act as the linking “nodes” to connect the thiols and
bring TACN-moieties in close proximity via strong AgÀ S bond.
Subsequent addition of Zn2+-ions would lead to complexation
by TACN and activate the system for catalysis. It was expected
that the catalytic activity could be modulated by the thiol alkyl
chain length. This expectation was based on the consideration
that the formation of an efficient catalytic pocket between
neighboring TACN·Zn2+-complexes would benefit from some
degree of conformational flexibility and the polarity of the local
environment. This very simple “mix-and-catalyse” method
would give access to a novel class of multivalent artificial
phosphatases.
With this procedure in mind, a series of thiols (HS-Cn-TACN)
bearing alkyl chains of various lengths (n=5–20) were synthe-
sized by a procedure which required three reaction steps[14] (see
SI, Figure S1). The substrate 2-hydroxypropyl-4-nitrophenyl
phosphate (HPNPP) was synthesized via a one-step ring-open-
ing reaction (Figure S2).[15] The synthesized thiols and HPNPP
were characterized by 1H NMR, 13C NMR and ESI-MS (SI). To
study whether the metal coordination polymers could be in situ
generated when Ag+- ions were mixed with the synthesized
thiols, a UV-vis titration experiment was carried out using HS-
C14-TACN (20 μM) in aqueous buffer ([HEPES]=10 mM, pH 8.0).
Before Ag+-ions were added, no absorption peaks appeared in
the measured wavelength window (200–550 nm). When Ag+
-ions were gradually introduced, a new absorption peak at a
wavelength of ~280 nm emerged and continued to increase in
intensity upon the further addition of Ag+-ions (Figure S3). This
band could be attributed to Ligand-to-Metal Charge Transfer
facilitated by argentophilicity.[13] The absorbance at 280 nm
linearly increased with increasing Ag+-ion concentration, but
reached a maximum value when the concentration reached
20 μM. The correspondence with the thiol concentration
(20 μM), together with the observation of a maximum at χ[HS-
C14-TACN]=0.5 in the Job’s plot (Figure S4), indicated the
formation of a structure with a 1:1 stoichiometry between Ag+
-ion and the thiol-moiety of HS-C14-TACN. The formation of a
coordination polymer was supported by DLS measurements,
which illustrated the presence of structures with an estimated
hydrodynamic diameter of around 41 nm (Figure S5). Further
experimental evidence for the formation of Ag-(S-C14-TACN)
coordination polymers was directly obtained from the observa-
tion of small fragments of the polymer in MALDI-TOF MS
experiments (Figure 2a). We found convincing evidence for the
formation of coordination polymers also in the Ag-(S-C5-TACN)
system (Figure S6). A worm-like morphology of Ag-(S-C14-TACN)
system was revealed by high resolution transmission electron
microscope (HRTEM, Figure S7) and scan electron microscope
(SEM, Figure S8). However, a clear metal lattice diffraction in the
selected diffraction area, which would have given unambiguous
proof for the polymers, was regrettably not observed.
To probe the difference in hydrophobic domains between
the structures, fluorescence titrations were carried out using the
fluorescent dye, Nile Red (Figures S9–10). Increasing amounts of
Ag-(S-Cn-TACN) (n=5À 16) were titrated to a fixed amount of
dye (5 μM) in the presence of Zn2+. It was observed that an
increase in the alkyl chain length (Cn) led to an enhanced
affinity for Nile Red, evidenced by a more efficient uptake of
dye at lower polymer concentrations. These results suggested
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hardly any increase in absorption at ~400 nm under similar
experimental conditions (Figure S13). These observations illus-
trate that all three components, i.e. HS-C14-TACN, Ag+-ion and
Zn2+-ion are required to obtain a functional multivalent catalyst
for the cleavage of HPNPP.
Considering the importance of two different kinds of metal
ions in defining the structure and activity of the system, we
investigated their possible substitution with other metal ions.
When Ag+-ions were substituted by other metal ions, fixing
Zn2+-ions as the second metal ion, catalytic activity was only
observed for Cd2+, Cu2+, and Zn2+-ions, but far lower than that
observed for Ag+-ions (Figure 3a). Similarly, when Zn2+-ions
were substituted by other metal ions, fixing Ag+-ions as the
firstly added metal ions, only the systems with Cu2+, Cd2+, Co2+
and Ni2+-ions demonstrated catalytic activity, but also in this
case far lower than that of the Zn2+-system (Figure 3b). These
results further supported the role of Ag+-ions in creating
polymeric structure and the role of Zn2+-ions in creating
catalytic pockets. A study of the catalytic activity as a function
of pH in Ag-(S-C14-TACN)-Zn2+ system showed a bell-shaped
profile with an apparent pKa of ca. 8.0 which is similar to that
observed for a related Au nanoparticle-based system reported
by Scrimin’s group[12] (Figure S14).
The saturation profile obtained when plotting the initial rate
as a function of substrate concentration could be fitted to the
MichaelisÀ Menten equation to afford a KM value of 0.13�
0.001 mM and a kcat value of 0.014�0.0003 sÀ 1 for the cleavage
of HPNPP by the Ag-(S-C14-TACN)-Zn2+ system (Figure 4a).
Therefore, the corresponding second-order rate constant (k2 =
kcat /KM) was calculated as 109�3 MÀ 1 sÀ 1 which is more than
15000 times higher than that of the mononuclear metal
complex catalyst with a TACN head (k2 =0.007 MÀ 1 sÀ 1) thus
lacking structural elements capable of bringing the two metal
ions in close proximity.[10a] It is also far higher than the value
reported for a dinuclear Zn2+ complex (k2 of 0.25 MÀ 1 sÀ 1),[17] for
vesicular assemblies with similar alkyl chain length (k2 of
5.7 MÀ 1 sÀ 1),[8b] and even for the inclusion complex formed by γ-
Figure 2. (a) MALDI-TOF result of Ag-(S-C14-TACN) system (the molar ratio of
Ag+-ion to HS-C14-TACN was 1:1); (b) The relationship between Zn2+-ion
concentration and absorbance at 400 nm in the hydrolysis of HPNPP
catalyzed by Ag-(S-C14-TACN)-Zn2+ system. Experiment conditions: [HS-C14-
TACN]=20 μM, [Ag+]=20 μM, [HPNPP]=80 μM; 10 mM HEPES buffer
°
solution of pH of 8.0; temperature of 37 C; reaction time of 30 min.
an increased hydrophobicity of the system upon an increase of
the length, n, of the alkyl chain.Next, kinetic titration experi-
ments were carried out to evaluate whether the complexation
of Zn2+-ions by the TACN-macrocycles would activate the
systems for catalysis. The first experiment consisted in the
measurement of p-nitrophenol (PNP) release upon the addition
of an equimolar amount of Zn2+-ions (20 μM) to a solution of
the Ag-(S-C14-TACN) coordination polymer ([TACN]=20 μM) in
the presence of the substrate 2-hydroxypropyl-p-nitrophenyl
phosphate (HPNPP, 80 μM). We were pleased to observe that
the absorbance at 400 nm gradually increased in time (Fig-
ure S11) indicating that the self-assembled structure is capable
of cleaving HPNPP.[9] A kinetic equivalent of a Job’s plot
revealed the highest catalytic activity when TACN and Zn2+
-ions were present in a 1:1 molar ratio (Figure S12). Further-
more, the observation of a sigmoidal reactivity profile when
increasing amounts of Zn2+-ions were added to a constant
concentration of Ag-(S-C14-TACN) indicated that the catalysis
should originate from the cooperative effect between two
adjacent TACN·Zn2+ complexes (Figure 2b), similar to that
observed for related multivalent systems.[16] Importantly, a series
of control experiments involving mixtures of Ag+ +HPNPP,
Zn2+ +HPNPP, HS-C14-TACN+Ag+ +HPNPP, HS-C14-TACN+
Zn2+ +HPNPP, HS-C14-TACN+HPNPP, and just HPNPP, revealed
Figure 3. The comparison of absorbance at 400 nm in the presence of HS-
C14-TACN and HPNPP, (a) the identity of the first metal ion was varied while
the second metal ion was fixed as Zn2+-ion; and (b) the first metal ion was
fixed as Ag+-ion while the identity of the second metal ion was varied. M or
Mn+ =1. Ag+; 2. Zn2+; 3. Cd2+; 4. Cu2+; 5. Co2+; 6. Ni2+; 7. Na+; 8. K+; 9. Fe3+
;
10. Al3+; 11. Cr3+; 12. Hg2+. Experimental conditions: [thiol]=20 μM; [metal
°
ion]=20 μM; [HPNPP]=80 μM; temperature of 37 C; mixing time of catalyst
with HPNPP of 30 min.
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chemical shift at À 5.09 ppm, originated from HPNPP gradually
decreased, while a new signal at 17.75 ppm, attributed to that
of cyclic phosphate, appeared and increased in time (Fig-
ure S16). On the other hand, the signal of À 5.09 ppm of HPNPP
remained almost unchanged in the absence of Ag-(S-C14-TACN)-
Zn2+ (Figure S17). Dialysis experiments showed that the
absorbance at 400 nm of HPNPP solution in Ag-(S-C14-TACN)-
Zn2+ system gradually decreased with increasing dialysis time
(Figure S18), which further supports the fact that this absorp-
tion peak originates from PNP anion rather than from other
species, such as Ag-nanoparticles. Observation of the anion by
ESI-MS measurements afforded further evidence for catalytic
substrate hydrolysis reaction(Figure S19). Finally, we also inves-
tigated the change in initial rate of HPNPP-transphosphoryla-
tion upon treating the coordination polymer with increasing
amounts of the reducing agent NaBH4 before adding Zn2+-ions.
It was found that the initial rate substantially decreased with
increasing NaBH4 concentrations, eventually reaching a final
level when the NaBH4 concentration exceeded 400 μM (Fig-
ure S20). HRTEM experiments revealed that small and uniform
Ag nanoparticles with average size of ~2 nm had formed under
the reducing conditions imposed by NaBH4 (Figure S21). Control
experiments indicated that the decrease in initial rate was not
caused by BO2À anions, as no significant inhibition effect on the
Figure 4. Reaction rate of HPNPP cleavage catalyzed by Ag-(S-C14-TACN)-
Zn2+ system as a function of HPNPP concentration (a), the relationship
between KM (b), kcat (c), k2 (d) and alkyl chain length (Cn is from 5 to 20).
Experimental condition: [Ag-(S-Cn-TACN)-Zn2+]=20 μM (the molar ratio of
Ag+-ion to thiol to Zn2+-ion was fixed as 1:1:1); [HPNPP]=80 μM; temper-
°
ature of 37 C; 10 mM HEPES buffer solution of pH 8.0. The solid line in (a) is
the fitted MichaelisÀ Menten equation curve. The dot lines in (b), (c), and (d)
are the change tendency guided by eyes.
cyclodextrin (γ-CD) and a bimetallic Zn2+ complex (k2 of
3.6 MÀ 1 sÀ 1).[16a] Interestingly, the k2-value of this system is
comparable to, or even higher than, those reported for
monolayer-passivated Au nanoparticles containing TACN-Zn2+
complexes (k2 of 81.6 MÀ 1 sÀ 1 and 4.4 MÀ 1 sÀ 1).[10a,18] The compa-
rative values reported in Table 1, clearly reveal that the in situ
formed Ag-(S-C14-TACN)-Zn2+ polymer system is an excellent
catalyst for HPNPP cleavage. The high reactivity is ascribed to
the in situ formation of a AgÀ S coordination polymer, which
serves as multivalent scaffold that for compacting the TACN-
Zn2+ complexes attached to flexible chains in close proximity,
thus creating “catalytic pockets” that can express cooperativity.
To further study the catalytic properties, several additional
experiments were performed. The periodic batch-wise addition
of HPNPP revealed that after each addition of 40 μM HPNPP
into a 40 μM Ag-(S-C14-TACN)-Zn2+ solution, the absorbance at
400 nm gradually increased to a saturating value. The ability to
repeat 6 cycles shows that the system displays substrate
turnover, which provides evidence for the catalytic nature of
Ag-(S-C14-TACN)-Zn2+ (Figure S15). It is noted that the reaction
rate progressively slowed down, which likely originated from
the inhibition effect of the anionic cyclic phosphate. Reaction
time-dependent 31P NMR experiments demonstrated that the
catalytic reaction was observed when BO2 anions were added
À
to the reaction mixture. These observations demonstrate that
the catalytic reactivity of the Ag-(S-C14-TACN)-Zn2+ coordination
polymers is higher than that of the corresponding Ag@(S-C14-
TACN)-Zn2+ nanoparticle system.
Previous studies on related Au NP systems have revealed
that the alkyl chain length plays an important role in
determining the catalytic activity of the system.[12] To inves-
tigate to which extent the catalytic activity of the Ag-SR
coordination polymers would be affected by structural changes,
thiols containing hydrophobic alkyl chains with lengths varying
from C5 to C20 and terminating with a TACN group were
employed. As shown in Figure S5, the hydrodynamic diameters
of Ag-(S-Cn-TACN) determined by DLS showed a significant
enhancement with increasing the thiol chain length.[19] This
indicates that the size of in situ formed Ag-SR coordination
polymers could possibly increase for increasing thiol chain
lengths. The complexation between other thiols and Ag+-ions
via strong AgÀ S bond was supported by UV-vis absorption
spectral titration, featured by a molar ratio of 1:1 (Figure S22).
Michaelis-Menten saturation kinetics were measured to deter-
mine the effect of the increased alkyl chain length on the
catalytic parameters. Intriguingly, the KM values, which are the
reciprocal of the affinity constants of the substrate HPNPP for
the catalyst, do virtually not vary as a function of the length of
the hydrophobic chain. This indicates that hydrophobic inter-
actions contribute little to substrate binding, which appears
therefore more driven by electrostatic interactions. On the other
hand, the kcat values significantly increase with increasing the
alkyl chain length. The maximum value is observed for C14,
which is ca. 5-fold higher than the lowest value (Figure 4c,
Table S1). The significant difference in kcat likely results from the
polarity difference in the pseudophase formed by the hydro-
Table 1. Comparison of KM, kcat, and k2 for HPNPP cleavage in the presence
of Ag-(S-C14-TACN)-Zn2+ system and other reported catalyst systems
Catalyst
KM / mM
k
cat / sÀ 1
k2 / MÀ 1.sÀ 1
Dinuclear complex 17
16
0.0041
0.003
0.031
0.0042
0.012
0.25
5.7
81.6
4.4
3.6
109
C18-TACN.Zn2+ 8b
0.53
0.38
0.93
3.3
Au NP-(S-C10-TACN).Zn2+ 18
Au NP-(S-C8-TACN).Zn2+ 10a
Bimetallic complex-γ-CD 16a
Ag-(S-C14-TACN).Zn2+ (this work)
0.13
0.0137
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Acknowledgements
This work was supported by the Fujian Provincial Department
of Science and Technology (No. 2020Y0038), the Xiamen
Municipal Bureau of Science and Technology
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Conflict of Interest
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The authors declare no conflict of interest.
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Keywords: Artificial phosphatases · homogeneous catalysis ·
Ag-SR coordination polymers · self-assembly · supramolecular
chemistry
24, 2814.
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rough estimates for the diameter to detect the trend in size change of
Ag-(S-Cn-TACN) as a function of the alkyl chain length.
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Manuscript received: January 29, 2021
Accepted manuscript online: April 19, 2021
Version of record online: ■■■, ■■■■
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www.chemeurj.org
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COMMUNICATION
A series of self-assembled multivalent
Ag-SR coordination polymers with
high phosphatase-like activity have
been developed. This work represents
a new alternative for the future
rational design of highly efficient
catalysts for hydrolysis of phosphates
and carboxylates.
Y.-J. Cao, M.-X. Yao, Prof. L. J. Prins, R.-
X. Ji, N. Liu, Prof. X.-Y. Sun, Prof. Y.-B.
Jiang*, Prof. J.-S. Shen*
1 – 6
Self-Assembled Multivalent Ag-SR
Coordination Polymers with Phos-
phatase-Like Activity