Tailored interactions of the secondary coordination sphere enhance the hydrolytic activity of crosslinked microgels

1. Tailored Interactions of the Secondary Coordination Sphere
Enhance the Hydrolytic Activity of Cross-Linked Microgels
Babloo Sharma and Susanne Striegler*
Department of Chemistry and Biochemistry, University of Arkansas, 345 North Campus Drive, Fayetteville, Arkansas 72701, United
States
*S Supporting Information
ABSTRACT: A series of mannose-templated microgels with
immobilized catalytic sites and catalysis-supporting co-monomers
was synthesized and evaluated for catalytic hydrolyses of glycosidic
bonds. Interactions of the secondary coordination sphere around
the catalytic center were implemented between the sugar and
surrounding monomers by copolymerization of corresponding
acrylates. The obtained microgels were evaluated for their ability to
enhance the catalytic hydrolysis of glycosidic bonds in neutral and
alkaline solution. The catalytic proficiency of the microgels reaches
a remarkable value of 1.4 × 107
at neutral pH when hydrogen-
bond-accepting 2-methoxyethyl acrylate is embedded in 20 mol %
as a co-monomer, instead of butyl acrylate. The results indicate a
strong influence of hydrogen-bond-accepting co-monomers on the
stability of the transition state of glycoside hydrolyses in the
designed biomimetic catalysts. The overall performance of all microgels correlates very well with the calculated dipole moments
of the implemented co-monomers.
KEYWORDS: macromolecular catalyst, matrix effects, miniemulsion, polyacrylate microgels, hydrolysis, glycosides
1. INTRODUCTION
Glycosidases are among the most proficient enzymes known
that use a sophisticated combination of interactions to support
and stabilize the transition state of glycoside hydrolyses.1
While catalytically active amino acids, such as glutamic and
aspartic acids, are crucial for the catalytic turnover in both
retaining and inverting glycosidases,2,3
additional stabilizing
interactions with a myriad of other amino acids in the active
site are equally important. The glycon of a substrate is thereby
strongly stabilized by hydrogen bonding or electrostatic
interactions,4,5
while the aglycon frequently engages in π−π
or CH−π stacking, hydrogen bonding, and/or van der Waals
interactions.6,7
The synergy of all those contributions results in
highly proficient and selective catalysts.
To transfer the principles found in nature to biomimetic
catalysis and guide the development of efficient homogeneous
catalysts,8,9
stabilizing interactions beyond the first coordina-
tion sphere of a transition-metal complex are often
targeted.10−13
In this context, mimicking the variety of
contributions found in an active site of an enzyme into a
second coordination sphere close to the metal core of a
synthetic catalyst is of particular interest. Recent achievements
include catalyst development for efficient hydrogenations,14−17
studying the effect of hydrogen bonds on metal-mediated
oxygen activation,18
electrocatalytic reduction of nitrite19
and
oxidation of hydrogen,20
and α-alkylation of nitriles with
primary alcohols,21
among many others.10−12
Controlling
electronic and structural properties in a secondary coordina-
tion sphere are also crucial for the construction of supra-
molecular assemblies,22
such as molecular machines.23,24
To supplement studies of the catalytic performance of small-
molecular-weight entities that utilize their secondary coordi-
nation sphere,11,14,25,26
a polymerizable derivative of binuclear
copper(II) complex Cu2bpdpo (1)27
has been immobilized in
a microgel matrix consisting of ethylene glycol dimethacrylate
(EGDMA) and butyl acrylate.28,29
Complex 1 catalyzes the
hydrolysis of glycosidic bonds and discriminates monosacchar-
ides upon binding in aqueous alkaline solution (Scheme 1).27
Ultrasheering of the monomer mixture in aqueous alkaline
solution in the presence of SDS surfactant and decane as a
hydrophobe yields water-dispersed microdroplets.29
Ultraviolet
(UV) light initiated free-radical polymerization in the cold
provides water-dispersed microgels with diameters between
250 nm and 280 nm.29
To ensure proliferation of the
polymerization, despite the presence of Cu(II) ions, strongly
chelating monosaccharides and sugar derivatives are employed
as templates during material preparation to mask the
paramagnetic character of the metal ions.29,30
The resulting
templating effect contributes to the overall catalytic perform-
ance of the obtained macromolecular catalysts but does not
Received: November 26, 2018
Revised: January 7, 2019
Published: January 11, 2019
Research Article
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2. control it.30
Instead, significant contributions to the overall
catalytic proficiency of the microgels by the matrix surrounding
the metal complex are noted.30,31
These preliminary results
prompted a detailed study to elaborate the contributions of the
secondary coordination sphere of an immobilized metal
complex to the catalytic performance of hydrolytic microgels.
Consequently, interactions of a metal-complex-bound hydro-
philic template (here, mannose (2)), and its surrounding
matrix are examined (Chart 1).
Along these lines, the hydrophobic butyl acrylate is partially
substituted by acrylate co-monomers that enable hydrogen
bonding and electrostatic interactions. Acrylates that promote
CH−π or π−π stacking interactions, as well as strong
hydrophobic van der Waals interactions are included in this
study as controls. A very good correlation between the
hydrogen-bond-accepting ability of the acrylate co-monomers,
their dipole moments, and the catalytic proficiency of the
resulting microgels is observed, and the details of this study are
described below.
2. RESULTS AND DISCUSSION
2.1. Microgel Synthesis and Physical Characteriza-
tion. In previous studies by us and others,4,5,32,33
hydrogen-
bond-donating and hydrogen-bond-accepting, π−π and CH−π
stacking, and electrostatic and hydrophobic interactions were
identified as dominating effects during the stabilization of the
transition state of enzyme-catalyzed glycoside hydrolyses.34
To
transfer these observations into the design of biomimetic
catalysts, mannose-templated microgels with altered acrylate
co-monomers were synthesized. It was hypothesized that the
transition-state-stabilizing interactions in the man-made ma-
terial would increase by interactions in the second coordina-
tion sphere of the metal complex center. Those stabilizing
interactions were then implemented in the microgels by partial
substitution of the non-cross-linking butyl acrylate monomer.
Therefore, 20 mol % of the butyl acrylate (BA, 3a) monomer
were replaced by methoxyethyl acrylate (MEA, 3b), hydrox-
yethyl acrylate (HEA, 3c), heptafluorobutyl acrylate (HFBA,
3d), benzyl acrylate (BnA, 3e), dodecyl acrylate (DdA, 3f),
and carboxyethyl acrylate (CEA, 3g) in the prepolymerization
mixture (Chart 2). The catalytic center in the microgels was
generated as described by immobilization of 0.5 mol % of
polymerizable ligand VBbpdpo (L, 4) (Chart 3), and 1 mol %
of copper(II) acetate in the presence of 5 mol % of mannose
during material synthesis.30
All polymerizations were performed in the presence of 60
mol % EGDMA cross-linking agent, 20 mol % BA, 20 mol %
co-monomer, and 1 mol % styrene or 0.5 mol % of ligand
VB(bpdpo) (4) in 52 mM SDS/CAPS buffer solution at pH
10.50.29,30
The gravimetric analyses of the polymerization
proceedings reveal a slightly faster progression of the initial
polymerization when polar comonomers CEA (3g) and MEA
(3b) are used, in comparison to microgel formulations in the
presence of BA (3a) or BnA (3e) (Figure 1). All reactions near
completion close to 60 min and reach 95% on average,
independently of the co-monomers used. Initial attempts to
analyze the synthesized microgels using IR and 1
H NMR
spectroscopy were futile and did not provide evidence for the
incorporation of the co-monomers (see the Supporting
Information). However, combustion data of microgels, purified
Scheme 1. Coordination of Cu2bpdpo (1) to Mannose
Chart 1. Interactions of the Metal Complex 1 in (a) the First
and (b) the Second Coordination Sphere
Chart 2. Acrylate Monomers 3a−3g
Chart 3. Ligand VB(bpdpo) (4)
Figure 1. Gravimetric analysis of polymerization proceedings for
microgels derived from 60 mol % EGDMA, 20 mol % BA, and 20
mol % co-monomer, i.e., BA (3a (orange ◮)), MEA (3b (red ◑)),
BnA (3e, green ◮)), and CEA (3g, ◨)).
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3. by dialysis, reveal near quantitative incorporation of the co-
monomers and the polymerizable ligand 4 that builds the
backbone of the catalytic center after activation of the dormant
catalyst with Cu(II) ions (Table 1).29,30
An analysis of the microgels by dynamic light scattering
(DLS) suggests, for all particles, hydrodynamic diameters Dh
between 243 nm and 283 nm, monomodal distributions, and
moderate dispersity. Correlations between the polarity of the
co-monomer and the resulting particle sizes are not apparent.
2.2. Evaluation of the Catalytic Performance of the
Microgels in Dependence of Their Matrix Composition.
The catalytic proficiency of microgels with altered matrix
composition was determined using the hydrolysis of 4-
Methylumbelliferyl-α-D-mannopyranoside (5) as model sub-
strate yielding mannose (2) and 4-methylumbelliferone (6) in
50 mM HEPES buffer at pH 7.0 (Scheme 2). The ease of
hydrolysis of the α-mannoside renders this substrate ideal for
fast catalyst screening in 96-well plate assays. The kinetic
parameters for the rate constant (kcat) and Michaelis−Menten
constants (KM) were determined by standard proce-
dures,30,35−37
and the catalytic efficiency (kcat/KM) and
proficiency (kcat/KM × knon) of the microgels were derived
therefrom (Table 2).
While the apparent rate constants for the microgel-catalyzed
hydrolyses of substrate 5 are fairly similar, the corresponding
Michaelis−Menten constants reveal different binding affinities
between 5 and the respective microgels that differ by up to 1
order of magnitude (Table 2, entries 1 and 2). Because of these
differences, a 5-fold higher catalytic proficiency results for
matrices incorporating 20 mol % of MEA 3b in place of BA 3a.
This observation indicates strong stabilizing interactions
between the MEA monomer and substrate 5 during the
transition state of the glycoside hydrolysis and verifies the
underlying hypothesis of this work. Given the free hydroxyl
groups in the glycon of 5, hydrogen-bond-accepting inter-
actions of 3b were attributed to cause the observed
stabilization of the glycoside during its hydrolysis. Similar
interactions of 5 with the monomers in the matrix are noted
for microgels containing hydroxyethyl acrylate 3c, although to
a much lesser extent. By contrast, the catalytic proficiency of
microgels derived from acrylates 3d−3g is within experimental
errors similar to that of microgels derived from 3a only. This
observation indicates a lack of significant additional inter-
actions by 3d−3g over 3a that would stabilize the selected
glycoside during its hydrolysis by the microgel catalyst.
However, hydrogen-bond-accepting interactions could be
Table 1. Combustion Data of Microgels Derived from Different Co-monomers 3 and Resulting Concentrations of Immobilized
VBbpdpo (4)a
entry co-monomer Cexpected [%] Cfound [%] Hexpected [%] Hfound [%] Nexpected [%] Nfound [%] VBbpdpo [mM]
1 BA (3a) 62.28 62.00 7.81 7.80 0.16 0.15 0.70
2 MEA (3b) 60.75 60.32 ± 0.01 7.49 7.50 ± 0.02 0.16 0.16 ± 0.03 0.79
3 HEA (3c) 60.34 59.69 ± 0.05 7.38 7.18 ± 0.06 0.16 0.17 ± 0.07 0.84
4 HFBA (3d) 54.36 55.15 ± 0.07 6.05 6.06 ± 0.06 0.14 0.15 ± 0.04 0.87
5 BnA (3e) 63.93 63.49 ± 0.08 7.22 7.13 ± 0.07 0.16 0.16 ± 0.03 0.89
6 DodecylA (3f) 64.96 64.41 ± 0.06 8.49 8.59 ± 0.05 0.14 0.15 ± 0.04 0.88
7 CEA (3g) 59.73 59.49 ± 0.08 7.14 7.42 ± 0.07 0.16 0.15 ± 0.03 0.78
a
The data are given as an average of combustion analyses of duplicate microgel formulations; the microgels are derived from 60 mol % EGDMA,
0.5 mol % VBbpdpo (4), 20 mol % BA, and 20 mol % of selected co-monomer.
Scheme 2. Catalyst Screening by Monitoring the Hydrolysis of 4-Methylumbelliferyl α-D-Mannopyranoside (5) Using Microgel
Catalysts with Altered Matrix Composition
Table 2. Kinetic Parameters, Catalytic Efficiency, and Catalytic Proficiency for the Hydrolysis of 5 Catalyzed by Microgels
Containing Different Co-monomers 3, and by Cu2bpdpo (1) in 50 mM HEPES Buffer, pH 7.00, and 37 °C
entry catalyst with (co-monomer) kcat [× 10−5
min−1
] KM [mM] kcat/KM [min−1
M−1
] kcat/(knon × KM)a
1 Cu
2
L
P (3a) 8.0 ± 0.2 4.51 ± 0.02 0.018 2 300 000
2 Cu
2
L
P (3b) 5.0 ± 0.4 0.46 ± 0.01 0.11 14 000 000
3 Cu
2
L
P (3c) 8.0 ± 0.3 2.40 ± 0.02 0.033 4 300 000
4 Cu
2
L
P (3d) 5.0 ± 0.3 2.41 ± 0.04 0.021 2 700 000
5 Cu
2
L
P (3e) 11 ± 0.2 7.43 ± 0.02 0.015 1 900 000
6 Cu
2
L
P (3f) 9.0 ± 0.3 8.47 ± 0.05 0.011 1 400 000
7 Cu
2
L
P (3g) 7.0 ± 0.5 6.64 ± 0.07 0.011 1 400 000
8 Cu
2bpdpo 0.36 ± 0.08 7.90 ± 0.90 0.00039 51 000
a
knon = 7.7 × 10−9
min−1
M−1
.
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4. also promoted by the highly fluorinated monomer 3d, yet the
performance of the corresponding microgel catalyst is not very
different from that of the microgel prepared with 3a.
Therefore, we calculated the dipole moments of all monomers
3a−3g in aqueous solution with density functional theory
(DFT) employing the continuous solvation model (COSMO)
for water, the B3LYP functional, and the 6-31+G(d) basis
set.38−40
All computations were performed with the PQSmol
suite yielding low energy conformers of the monomers at
298.15 K and 1 atm.40
Vibrational analyses confirmed the
energy minima of the computed structures with zero imaginary
frequency (see the Supporting Information). The dipole
moments of MEA and HEA are notably higher than those of
all other monomers and correlate well with the increased
catalytic proficiency of the corresponding microgels (Figure 2).
Given the apparent correlation between catalytic proficiency
and dipole moment of the comonomers, we calculated the
dipole moment of the sodium salt of CEA as 6.2.
Consequently, a CEA-containing microgel should show, in
alkaline solution, a catalytic proficiency that is higher than that
of a microgel with BA only.
Since the dissociation constant of CEA in water, to the best
of our knowledge, is not reported, we used the structural
similarity between CEA and propionic acid to predict the pKa
value of CEA as 4.9.41
We then projected the pKa value of a
linear CEA polymer as 5.6, and estimated the pKa value of a
cross-linked microgel with 20 mol % of CEA as 10.1 following
the method by Fisher and Kunin as described.42
In short, the
apparent pKa values of cross-linked microgels were estimated
from the pKa(m=1) value of a linear polymer of the monomeric
acid as
K K mp p (2 )ma,app a( 1)= −= (1)
where m is the mole fraction of the monomeric acid.42
The
dissociation constant of the linear polymer is estimated
graphically by extrapolation.42
We subsequently determined the catalytic performance of all
microgels in 50 mM CAPS buffer at pH 10.50 (Table 3). The
alkaline conditions increase the amount of deprotonated CEA
monomer from <1% at pH 7.00 to more than 71% at pH
10.50. As the uncatalyzed hydrolysis of substrate 5 increases by
the change of conditions 150-fold as well, the resulting catalytic
proficiencies of the microgel catalysts decrease overall. For a
fair comparison of catalytic performances under different
conditions, we thus calculated the catalytic proficiencies,
relative to their low-molecular-weight complex Cu2bpdpo (1)
(Figure 3).
Under alkaline conditions, the catalytic proficiency of the
microgels increases to 36, relative to the performance of
complex Cu2bpdpo (1), whereas it was only 27-fold higher at
neutral pH. However, the corresponding MEA-containing
microgel has a 275-fold higher relative catalytic proficiency
than Cu2bpdpo (Table 2, entry 2) rendering the incorporation
of CEA in microgels to increase the catalytic turnover during
glycoside hydrolyses under these conditions less efficient.
■ CONCLUSIONS
A small selection of mannose-templated polymers with 60
mol % of cross-linking content was synthesized embedding
equal molar amounts of butyl acrylate and supplementary
acrylate co-monomers. The co-monomers introduced secon-
dary interactions in the microgel matrix, such as hydrogen-
bond-donating and hydrogen-bond-accepting, hydrophobic,
π−π stacking, and electrostatic interactions.. The obtained
microgels were then evaluated for their ability to enhance the
hydrolysis of glycosidic bonds in neutral and alkaline solution.
Figure 2. Catalytic proficiency (orange bar) of selected microgels and
dipole moments (green diamonds) of corresponding comonomers
during the hydrolysis of 5 in 50 mM HEPES buffer at pH 7.00 and 37
°C.
Table 3. Kinetic Parameters, Catalytic Efficiency, and Catalytic Proficiency for the Hydrolysis of 5 Catalyzed by Microgels
Containing Different Co-monomers 3 in 50 mM CAPS Buffer, pH 10.50, and 37 °C
entry co-monomer kcat [× 10−3
min−1
] KM [mM] kcat/KM [min−1
M−1
] kcat/(knon × KM)a
1 BA30
(3a) 2.2 ± 0.50 8.7 ± 0.9 0.26 232 000
2 MEA (3b) 1.8 ± 0.10 6.1 ± 0.7 0.30 269 000
3 HEA (3c) 1.8 ± 0.07 6.8 ± 0.4 0.27 236 000
4 HFBA (3d) 3.1 ± 0.43 17.2 ± 0.7 0.18 159 000
5 BnA (3e) 2.5 ± 0.22 11.8 ± 1.0 0.21 187 000
6 DdA (3f) 2.0 ± 0.10 7.8 ± 0.5 0.26 230 000
7 CEA-Na (3g-Na) 2.2 ± 0.20 8.2 ± 1.3 0.27 242 000
a
knon (1.13 × 10−6
min−1
M−1
);30
kcat/(knon × KM) for Cu2bpdpo = 6800.30
Figure 3. Catalytic proficiency of a microgel with 20 mol % CEA at
pH 7.00 and 10.50 and 37 °C, relative to Cu2bpdpo (1).
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5. The catalytic proficiency of the resulting microgels was
notably enhanced in neutral solution in the presence of 20
mol % of MEA comonomer (3b) reaching 1.4 × 107
, and to
some smaller extend by HEA (3c). A contribution to the
hydrolysis of glycosidic bonds by all other assessed
comonomers 3d−3g was not apparent under these conditions
and close to the performance of the standard, i.e., the microgel
prepared from butyl acrylate (3a) monomer only. This
observation correlates well with the calculated dipole moments
of the co-monomers and their hydrogen-bond-accepting
ability. By contrast, contributions of electrostatic interactions
promoted by a CEA-containing microgel are only apparent in
highly alkaline solutions reflecting the increased pKa value of a
protic monomer in a cross-linked matrix.42
3. EXPERIMENTAL SECTION
Microgel Synthesis. All microgels were prepared with 60
mol % EGDMA, 20 mol % BA, and 20 mol % of co-monomer,
i.e., butyl acrylate (BA, 3a), 2-methoxyethyl acrylate (MEA,
3b), 2-hydroxyethyl acrylate (HEA, 3c), 2,2,3,3,4,4,4-hepta-
fluorobutyl acrylate (HFBA, 3d), benzyl acrylate (BnA, 3e),
dodecyl acrylate (DdA, 3f), carboxyethyl acrylate (CEA, 3g) in
the presence of 0.5 mol % of VBbpdpo (4), 1 mol % copper(II)
acetate and 5 mol % mannose, following a previously described
protocol for photoinitiated polymerization at 3 °C.29,30
Kinetic Data. Typically, the product formation observed
within the first 200 min was used for analysis of the kinetic
data. Catalyst inactivation due to product inhibition was
observed after 6 h.
■ ASSOCIATED CONTENT
*S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.8b04740.
Microgel characterization by DLS, IR, and NMR
spectroscopy, as well as computation of dipole moments
for all co-monomers (PDF)
■ AUTHOR INFORMATION
Corresponding Author
*Tel.: +1-479-575-5079. Fax: +1-479-575-4049. E-mail:
Susanne.Striegler@uark.edu.
ORCID
Babloo Sharma: 0000-0002-0265-322X
Susanne Striegler: 0000-0002-2233-3784
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
Support of this research to S.S. from the Arkansas Biosciences
Institute is gratefully acknowledged.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
The authors thank Peter Pulay for advice and access to PQS
mol and Ifedi Orizu for recording of 1
H NMR spectra.
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ACS Catalysis Research Article
DOI: 10.1021/acscatal.8b04740
ACS Catal. 2019, 9, 1686−1691
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