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Tailored interactions of the secondary coordination sphere enhance the hydrolytic activity of crosslinked microgels Babloo Sharma, and Susanne Striegler ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04740 • Publication Date (Web): 11 Jan 2019 Downloaded from http://pubs.acs.org on January 13, 2019
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ACS Catalysis
Tailored interactions of the secondary coordination sphere enhance the hydrolytic activity of crosslinked microgels Babloo Sharma, and Susanne Striegler* Department of Chemistry and Biochemistry, University of Arkansas, 345 North Campus Drive, Fayetteville 72701, Arkansas, United States 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 remarkable 1.4 × 107 at neutral pH when H-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 H-bond accepting comonomers 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.
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 H-bonding or electrostatic interactions,4-5 while the aglycon frequently engages in - or CH- stacking, H-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 into biomimetic catalysis and guide the development of efficient homogeneous catalysts,8-9 stabilizing interactions beyond the first coordination 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 hydrogenations14-17, studying the effect of H-bonds on metalmediated oxygen activation,18 electrocatalytic reduction of nitrite19 and oxidation of hydrogen,20 and -alkylation of nitriles with primary alcohols21 among many others.10-12 Controlling electronic and structural properties in a secondary coordination sphere are also crucial for the construction of supramolecular assemblies,22 such as molecular machines.23-24 To supplement studies of the catalytic performance of small molecular weight entities that utilize their secondary coordination 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 ethyleneglycol dimethacrylate (EGDMA) and butyl acrylate.28-29 Complex 1 catalyzes the
hydrolysis of glycosidic bonds and discriminates monosaccharides upon binding in aqueous alkaline solution (Scheme 1).27 2+ N Cu
HN
OH O OH2
HN
Cu N
OH
OH2 HO HO
OH O OH
HO HO CAPS buffer, pH 10.50
HO HO
Cu
2+
O Cu O
OH2
Scheme 1. Coordination of Cu2bpdpo (1) to mannose Ultra-sheering of the monomer mixture in aqueous alkaline solution in presence of SDS surfactant and decane as a hydrophobe yields water-dispersed microdroplets.29 UV-light initiated free radical polymerization in the cold provides waterdispersed microgels with diameters between 250 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 performance of the obtained macromolecular catalysts, but it does not 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 hydrophilic
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ACS Catalysis template, here mannose (2), and its surrounding matrix are examined (Chart 1).
(a)
Along these lines, the hydrophobic butyl acrylate is partially substituted by acrylate co-monomers that enable H-bonding and electrostatic interactions. Acrylates that promote CH- or - stacking interactions as well as strong hydrophobic van-der-Waals interactions are included in this study as controls. A very good correlation between the H-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.
(b)
H
O H
H HO OO
2+
Cu
H
O
Cu
O
All polymerizations were carried out in presence of 60 mol% EGDMA crosslinking 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 co-monomers CEA (3g) and MEA (3b) are used in comparison to microgel formulations in 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 1H NMR spectroscopy were futile and did not provide evidence for the incorporation of the co-monomers (See Supporting information). However, combustion data of microgels, purified 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
2+
Cu
O
Cu O
R (3)
O
In previous studies by us and others, 4-5, 32-33 H-bond donating and accepting, --and CH- 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 material would increase by interactions in the second coordination sphere of the metal complex center. Those stabilizing interactions were then implemented in the microgels by partial substitution of the non-crosslinking butyl acrylate monomer. Therefore, 20 mol% of the butyl acrylate (BA, 3a) monomer were replaced by methoxyethyl acrylate (MEA, 3b), hydroxyethyl acrylate (HEA, 3c), heptafluorobutyl acrylate (HFBA, 3d), benzyl acrylate (BnA, 3e), dodecyl acrylate (DdA, 3f) and carboxyethyl acrylate (CEA, 3g) in the pre-polymerization 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 presence of 5 mol% of mannose during material synthesis.30
H HO OO
Chart 1. Interactions of the metal complex 1 in (a) the first and (b) the second coordination sphere
2. Results and Discussion 2.1. Microgel synthesis and physical characterization
O H
O
R= O
(3a) F OH
(3e) COOH
(3b) F
(3c)
F
FF
FF
(3d)
(3f)
9
(3g)
Chart 2. Acrylate monomers 3a-g N
OH
H N
H N
(4)
OR
N
R= OR
Chart 3. Ligand VB(bpdpo) (4) 100
polymerization [%]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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75 50 25 0
0
30
60 time [min]
90
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. ), MEA (3b, ), BnA (3e, ), and CEA (3g, )
Table 1. Combustion data of microgels derived from different co-monomers 3 and resulting concentrations of immobilized VBbpdpo (4) Entry 1 2 3 4 5 6
Co-monomer BA (3a) MEA (3b) HEA (3c) HFBA (3d) BnA (3e) DodecylA (3f)
Cexpected [%] 62.28 60.75 60.34 54.36 63.93 64.96
Cfound [%] 62.00 60.32 ± 0.01 59.69 ± 0.05 55.15 ± 0.07 63.49 ± 0.08 64.41 ± 0.06
Hexpected [%] 7.81 7.49 7.38 6.05 7.22 8.49
Hfound [%] 7.80 7.50 ± 0.02 7.18 ± 0.06 6.06 ± 0.06 7.13 ± 0.07 8.59 ± 0.05
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Nexpected [%] 0.16 0.16 0.16 0.14 0.16 0.14
Nfound [%] 0.15 0.16 ± 0.03 0.17 ± 0.07 0.15 ± 0.04 0.16 ± 0.03 0.15 ± 0.04
VBbpdpo [mM] 0.70 0.79 0.84 0.87 0.89 0.88
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7 CEA (3g) 59.73 59.49 ± 0.08 7.14 7.42 ± 0.07 0.16 0.15 ± 0.03 0.78 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.
2.2 Evaluation of the catalytic performance of the microgels in dependence of their matrix composition
HO HO HO
HO
(5)
O
O
O
7
3
7
2
6
1
0.0
0
1.5x10 1.0x10 5.0x10
comonomer
Figure 2, Catalytic proficiency (orange bar) of selected microgels and dipole moments (green diamonds) of corresponding co-monomers during the hydrolysis of 5 in 50 mM HEPES buffer at pH 7.00 and 37°C.
HO HO HO
O
4
EA lA C y ec od D lA y nz Be
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 up to one order of magnitude (Table 2, entries 1&2). Due to 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, H-bond accepting interactions 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-g is within experimental errors similar to that of microgels derived from 3a only. This observation indicates a lack of significant additional interactions by 3d-g over 3a that would stabilize
7
2.0x10
dipole moment [D]
The catalytic proficiency of microgels with altered matrix composition was determined using the hydrolysis of 4methylumbelli-feryl--D-mannopyranoside (5) as model substrate yielding mannose (2) and 4-methylumbelliferone (6) in 50 mM HEPES buffer at pH 7.0 (Scheme 2). The ease of hydrolysis of the -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 procedures,30, 35-37 and the catalytic efficiency (kcat/KM) and proficiency (kcat/KM × knon) of the microgels were derived therefrom (Table 2).
the selected glycoside during its hydrolysis by the microgel catalyst. However, H-bond accepting interactions could be 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-g 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 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).
catalytic proficiency
An analysis of the microgels by dynamic light scattering suggests for all particles hydrodynamic diameters Dh between 243 and 283 nm, monomodal distributions, and moderate dispersity. Correlations between the polarity of the co-monomer and the resulting particle sizes are not apparent.
BA A FB H EA H EA M
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ACS Catalysis
HO
O
O
O
+
(2)
OH
(6)
H-bonds, eletrostatic, -stacking or hydrophobic interactions between polymer chains
Buffer, 37°C
Scheme 2. Catalyst screening by monitoring the hydrolysis of 4-methylumbelliferyl -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 1 2 3 4 5
Catalyst with (co-monomer) Cu LP(3a) 2 Cu LP(3b) 2 Cu LP(3c) 2 Cu LP(3d) 2 Cu LP(3e) 2
kcat × 10-5 [min-1]
KM [mM]
kcat/KM [min-1 M-1]
8.0 ± 0.2 5.0 ± 0.4 8.0 ± 0.3 5.0 ± 0.3 11 ± 0.2
4.51 ± 0.02 0.46 ± 0.01 2.40 ± 0.02 2.41 ± 0.04 7.43 ± 0.02
0.018 0.11 0.033 0.021 0.015
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kcat/(knon × KM) 2,300,000 14,000,000 4,300,000 2,700,000 1,900,000
ACS Catalysis Cu LP(3f) 2 Cu LP(3g) 2
6 7 8
Cu2bpdpo
9.0 ± 0.3 7.0 ± 0.5 0.36 ± 0.08
8.47 ± 0.05 6.64 ± 0.07 7.90 ± 0.90
0.011 0.011 0.00039
1,400,000 1,400,000 51,000
knon 7.7 × 10-9 min-1 M-1 Given the apparent correlation between catalytic proficiency and dipole moment of the co-monomers, we calculated the dipole moment of the sodium salt of CEA as 6.2. Consequently, a CEAcontaining microgel should show in alkaline solution a catalytic proficiency that is higher than that of a microgel with BA only. As the dissociation constant of CEA in water is to the best of our knowledge 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 crosslinked 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 crosslinked microgels were estimated from the pKa(m=1) value of a linear polymer of the monomeric acid as pKa, app = pKa(m=1) (2-m)
(1) acid.42
where m is the mol fraction of the monomeric 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 less than 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). 40
relative catalytic proficiency
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Conclusions A small selection of mannose-templated polymers with 60 mol% of crosslinking content was synthesized embedding equal molar amounts of butyl acrylate and supplementary acrylate comonomers. The co-monomers introduced secondary interactions in the microgel matrix, such as H-bond donating and accepting, hydrophobic, - 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. The catalytic proficiency of the resulting microgels was notably enhanced in neutral solution in 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 co-monomers 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 H-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 crosslinked matrix.42
3 Experimental
30
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), 2hydroxyethyl acrylate (HEA, 3c), 2,2,3,3,4,4,4-heptafluorobutyl acrylate (HFBA, 3d), benzyl acrylate (BnA, 3e), dodecyl acrylate (DdA, 3f), carboxyethyl acrylate (CEA, 3g) in 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
20 10 0
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 275fold 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.
1
1 6
8 pH value
10
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).
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 6h.
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
1 2 3 4 5 6 7
BA30 (3a) MEA (3b) HEA (3c) HFBA (3d) BnA (3e) DdA (3f) CEA-Na (3g-Na)
kcat × 10-3 [min-1] 2.2 ± 0.50 1.8 ± 0.10 1.8 ± 0.07 3.1 ± 0.43 2.5 ± 0.22 2.0 ± 0.10 2.2 ± 0.20
KM [mM] 8.7 ± 0.9 6.1 ± 0.7 6.8 ±0.4 17.2 ± 0.7 11.8 ± 1.0 7.8 ± 0.5 8.2 ± 1.3
kcat/KM [min-1 M-1] 0.26 0.30 0.27 0.18 0.21 0.26 0.27
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kcat/(knon × KM) 232,000 269,000 236,000 159,000 187,000 230,000 242,000
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knon (1.13 × 10-6 min-1 M-1)30; kcat/(knon × KM) for Cu2bpdpo = 6,80030
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ASSOCIATED CONTENT AUTHOR INFORMATION Corresponding Author Susanne Striegler, *Email:
[email protected]; phone: +1-479-575-5079; fax: +1-479-575-4049 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 Sources Support of this research to S.S. from the Arkansas Biosciences Institute is gratefully acknowledged. Supporting Information. Microgel characterization by DLS, IR and NMR spectroscopy as well as computation of dipole moments for all co-monomers. This material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT The authors thank Peter Pulay for advice and access to PQS mol and Ifedi Orizu for recording of 1H NMR spectra
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