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Computational Design and Preparation of MIPs for Atrazine Recognition on a Conjugated Polymer-Coated Microtiter Plate Dhana Lakshmi,*,‡ Meshude Akbulut,† Petya K. Ivanova-Mitseva,‡ Michael J. Whitcombe,‡ Elena V. Piletska,‡ Kal Karim,‡ Olgun Güven,† and Sergey A. Piletsky‡ †

Hacettepe University, Chemistry Department, Polymer Chemistry Division, 06800, Beytepe, Ankara, Turkey Cranfield Health, Vincent Building, Cranfield University, Cranfield, Bedfordshire, MK43 0AL, United Kingdom

‡

S Supporting Information *

ABSTRACT: Herein, we present a technique for the coating of microplate wells with thin layers of cross-linked polymers, as demonstrated by the preparation of a small library of molecularly imprinted polymers (MIPs) imprinted with atrazine and the corresponding control polymers (NIPs). The composition of MIPs was based on the results of a computational screening using the SYBYL suite of molecular modeling software. The monomers giving the most favorable interaction energies in a virtual monomers screening were N,N′-methylene-bis-acrylamide, methacrylic acid, N-phenylethylene diamine methacrylamide (NPEDMA), and itaconic acid. The polymer library was prepared by surface grafting to a layer of poly-(NPEDMA), formed by oxidative polymerization in each of the microplate wells, after activation of the methacrylamide double bonds with a photochemical iniferter (benzyl N,N-diethyldithiocarbamate). MIPs and NIPs were prepared with each of the four functional monomers, cross-linked with ethylene glycol dimethacrylate, using template-monomer ratios of 1:1, 1:2, or 1:3. Binding of the template and its structural analogs (simizine and metribuzine) was assessed by LC-MS. The method is shown to be suitable for rapid screening and optimization of MIPs, is capable of automation, and uses a simple grafting protocol compatible with conventional MIP compositions. The method not only can be used as a screening tool but could also form the basis of new MIPbased assays.

1. INTRODUCTION Synthetic receptors based on molecularly imprinted polymers (MIPs) are promising alternatives to natural receptors for a range of applications requiring specific and selective molecular recognition.1−4 Molecularly imprinted polymers (MIPs) are synthetic materials with artificially generated recognition sites able to rebind specifically a target molecule in preference to other closely related compounds. These materials are obtained by the polymerization of functional and cross-linking monomers in the presence of template molecules, leading to highly cross-linked three-dimensional network polymers bearing a spatial and chemical “memory” for the template. The performance of MIPs in terms of their recognition properties, for applications such as analytical separations, is dependent upon a number of factors, in particular the nature of the functional monomer and its stoichiometry with respect to the template. Other important parameters include the solvent, method of polymerization, polymerization temperature, and nature and extent of cross-linking. There are a number of approaches taken in order to find the optimum MIP composition or synthesis conditions for any particular application. These include computational methods,5−9 chemoinformatics-based “design of experiment” approaches10−12 and combinatorial screening.13−17 In terms of the latter set of methods, the format of the polymer may also have a bearing on its final application and its ease of preparation. Early methods relied on the preparation of “miniMIPs” as small scale models of monoliths, a traditional but increasingly obsolete format of imprinted polymers, in the form of layers of MIP (or NIP) formed at the bottom of HPLC vials.14,15 More recently © XXXX American Chemical Society

developed approaches have focused on the preparation of specific morphologies such as microbeads, formed by a suspension polymerization approach18,19 or within microfluidic reactors.17 The beaded format enables more rapid washing, separation, and testing of MIP performance, this can also be achieved within solid-phase extraction (SPE) cartridges,19 such that isolation and testing of the material could be carried out in situ. A similar in situ preparation and testing could be achieved using MIPs coated on the walls of microtiter plates. This communication describes our initials experiments aimed at showing the feasibility of such a design. Thin MIP films are particularly common in sensor applications,20 in the modification of membrane surfaces21 and in some extraction technologies, such as MIP-coated microextraction fibers22,23 and MIP-coated stirrer bars.24−26 In many cases, the formation of these coatings is achieved by a “grafting from” approach by activation of an initiator bound to the surface to be coated, thus avoiding wasteful polymerization in the bulk of the solution and resulting in localization of the imprinted coating on the surface of the fiber or transducer element. We recently showed that coatings of functional polymers could be prepared on the walls of microtiter plate Special Issue: Recent Advances in Nanotechnology-based Water Purification Methods Received: October 30, 2012 Revised: January 24, 2013 Accepted: January 24, 2013

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dx.doi.org/10.1021/ie302982h | Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

Industrial & Engineering Chemistry Research

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(NPEDMA), and itaconic acid (IA) (Figure 1) were used as functional monomers in different monomer/template ratios to prepare a MIP library over microplates modified with polyNPEDMA (Table 1).

wells by grafting to a layer of a modified polyaniline, bearing methacrylamide groups, and following activation with a photoiniferter, benzyl N,N-diethyldithiocarbamate;27 thus, it should be possible to prepare libraries of MIPs in the same way. Such a method of library formation would complement miniMIP and microbead-based methods as a combinatorial model for MIP thin films. Moreover, MIP-coated microplates can also form the basis of biomimetic assays28,29 and therefore have utility beyond screening tools. We have set out to demonstrate the feasibility of the preparation of a small library of MIPs and their corresponding NIP polymers in microtiter plate format.

2. EXPERIMENTAL SECTION Materials. N-phenylethylene diamine, methacrylic anhydride, ammonium persulfate (APS), hydrochloric acid (HCl), N,N-diethyl dithiocarbamic acid benzyl ester (DEDTC), ethylene glycol dimethacrylate (EGDMA), itaconic acid (IA), N,N′-methylene-bis-acrylamide (bisacrylamide), and methacrylic acid (MAA) were purchased from Sigma-Aldrich (Gillingham, U.K.). Atrazine was purchased from Riedel de Haën. Polystyrene microplates were from Nalge Nunc (Rochester, NY). All other chemicals and solvents used within this work were purchased from Sigma-Aldrich and were of analytical grade. Milli-Q distilled water was used in all experiments. Equipment. A Philips type HB 171/A self-tanning UV lamp, fitted with four CLEO 15 W UVA fluorescent tubes (Philips) with continuous output in the region 300−400 nm, delivering 0.09 W cm−2 at a distance of 8 cm, was used for UV irradiation. Sessile water contact angle (CA) measurements were made using Cam 100 optical Angle Meter (KSV Instruments Ltd., Finland) with the software provided. Optical densities were recorded using a microplate reader (MR700 Microplate Reader, Dinex Technologies Inc., Edgewood, NY) and by UV spectrophotometer (UV-1800 Schimadzu, Japan). Quantification of atrazine was carried out using a Waters 2975 HPLC system equipped with a C18 (2) column (50 × 3 mm, 3 μm, Phenomenex) by HPLC-MS. Computational Molecular Modeling. The combinatorial screening of the most suitable monomers for the preparation of MIPs for atrazine was carried out as described elsewhere for other templates.30 The rational design of MIPs was carried out on a PC running Linux executing the software package SYBYL 7.3 (Tripos Inc.). In silico screening was used to select the monomers showing the strongest interaction with the template based on the calculated binding energies. Molecular dynamics simulations and simulated annealing were also performed in order establish the likely monomer−template ratio giving rise to the highest affinity binding sites as a guide to the polymer composition. Synthesis of N-phenylethylenediamine (NPEDMA) Aniline-Based Monomer. NPEDMA was synthesized and characterized as reported in our previous work.31 Coating of Wells with Poly(NPEDMA) and Iniferter Attachment. Oxidative polymerization of NPEDMA and attachment of iniferter (N, N-diethyl dithiocarbamic acid benzyl ester) were performed as reported in our previous work.27 Photochemical Grafting of MIP and NIP Layers. Based on the molecular modeling results, four monomers were chosen for preparation of MIPs and nonimprinted polymers (NIPs) for atrazine. N,N′-methylene-bis-acrylamide (bisacrylamide), methacrylic acid (MAA), N-phenylethylene diamine methacrylamide

Figure 1. Structures of the template (atrazine) and the functional monomers: itaconic acid (IA); methacrylic acid (MAA); N-phenylethylene diamine methacrylamide (NPEDMA); and N,N′-methylenebis-acrylamide (bisacrylamide) used in this work.

Table 1. Composition of Monomers and Template for the Preparation of Mini-MIPs over Microplates Modified by PolyNPEDMA monomer: template monomer N,N-methylene bisacrylamide (MIP1) methacrylic acid (MIP2)

NPEDMA (MIP3)

itaconic acid (MIP4)

concn. of monomer (mM)

MIP

NIP

6.03 12.06 18.90 6.03 12.06 18.09 6.03 12.06 18.09 6.03 12.06 18.09

1:1 2:1 3:1 1:1 2:1 3:1 1:1 2:1 3:1 1:1 2:1 3:1

1:0 2:0 3:0 1:0 2:0 3:0 1:0 2:0 3:0 1:0 2:0 3:0

Ethylene glycol dimethacrylate (EGDMA) was the crosslinker (0.39 g, fixed amount for all polymers), atrazine (6.03 mM, in all MIP) and the porogen was acetonitrile (10 mL) in all cases. Polymerization mixtures comprising solutions of functional monomer (Table 1), EGDMA and atrazine (MIPs only) in 10 mL acetonitrile were purged with nitrogen for 5 min to remove oxygen and 200 μL of the mixtures were placed into the microplate wells using a multichannel pipet. Each composition was prepared in six replicates for each monomer composition on a microtiter plate. The microplate was placed inside a zip-lock plastic bag connected to a nitrogen inlet to maintain an inert atmosphere. Polymerization was carried out by irradiation for 25 min with a Philips UV lamp. After thorough washing with distilled water, the MIP-grafted microplates were dried and evidence of grafting was obtained by contact angle (CA) measurements. To remove template, microplates were washed with a solution of MeOH/acetic acid/water (0.9:0.1:1, v/v) (10 mL B



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2:1 complex, with a lower energy of formation, (−58.79 kcal mol−1). The corresponding complex of NPEDMA with atrazine always gave only 1:1 complexes. It appears, therefore, that bisacrylamide or itaconic acid could potentially be superior monomers for the imprinting of atrazine. This hypothesis can be conveniently tested in the proposed grafted thin-film miniMIP format within microtiter plate wells. Synthesis of the Polymer Library. In our previous work, we reported a method for the chemical polymerization of a new bifunctional monomer, N-phenylethylene diamine methacrylamide (NPEDMA), over microplates for various immobilization and diagnostic purposes.27 NPEDMA, which features both an aniline moiety and a methacrylamide group, can be polymerized to form polyanilines with methacrylamide groups as pendant side-chains. The double bond gives a convenient attachment point for vinyl polymerization and has proved useful in the preparation of electrochemical sensors20,35,36 and for grafting to other surfaces such as polystyrene.27 A convenient way of activating the poly(NPEDMA) surface to enable grafting is by UV irradiation in the presence of a photoiniferter such as a dialkyldithiocarbamate ester.20,37 This results in a low degree of polymerization at the surface due to the limited mobility of the methacrylamide groups. The “living” nature of iniferter-initiated polymerization means that the polymerization of a grafted layer is readily achieved from the polyaniline-macroiniferter. Poly(NPEDMA) thin films were coated onto the microtiter plate well using the previously optimized conditions: NPEDMA (39 mM), APS (42 mM) in 1 M HCl.27 Coating of 96 well microplates was performed for 90 min in the dark. Modified microplates were subsequently washed with 0.01 M HCl for 30 min and dried before photochemical coupling of the iniferter.27 The modified plates were used to generate MIP (and NIP) libraries for atrazine (see Table 1) by filling the coated wells with degassed solutions of polymerization mixtures followed by UV-initiated polymerization. The effectiveness of grafting of various MIPs and NIPs was confirmed by contact angle measurements (Figure S9, Supporting Information). All coatings were hydrophilic (CA < 90°), and as expected, the most hydrophilic monomers, methcrylic acid and itaconic acid, have the lowest contact angles [methacrylic acid, 59.2° (MIP) and 60.1° (NIP), and itaconic acid, 62.3° (MIP) and 62.2° (NIP)], respectively. The contact angle values for coated microplate wells were very similar for wells grafted with the same polymer, the standard deviation being below 5% in all cases. Evaluation of Atrazine-Binding to the Polymer Library. MIP-coated plates were tested for their ability to bind atrazine from aqueous solution (20% acetonitrile/water). The concentration of free atrazine in the microplate wells before and after incubation was analyzed using HPLC-MS. The purpose of screening was to correlate the results obtained by computational modeling and the mini-MIPs synthesized over microplates and to validate the method of thin-film mini-MIP synthesis. The four monomers (Table 1) were used for making a library of mini-MIPs grafted to microplates. For each monomer, 3 monomer/template ratios (1:1, 2:1, 3:1) were used. Each polymer composition was prepared as a set of six replicates in order to obtain high precision in the results. Analyses were also performed in triplicate. Figure 2 shows the binding of atrazine (200 ng mL−1) and its two structural analogs, simazine and metribuzine to the MIPs and NIPs prepared using 1:1 monomer/template ratio.

in total and/or until no signal for atrazine was detected by HPLC-MS). After washing with distilled water, the plate was dried and the CA measured. Binding Studies. A solution of atrazine in 20% acetonitrile−water (200 μL of 200 ng mL−1) was added to each well of a MIP-grafted microplate followed by incubation overnight at room temperature. After incubation, aliquots from each well were collected on a separate microplate and analyzed for atrazine content by HPLC-MS (mobile phase: methanol with 0.1% formic acid as additive). The run time was 5 min. The flow rate was 0.2 mL min−1, and the injection volume was 10 μL. The characteristic fragment of atrazine (m/z 174) was detected by mass-spectrometry using a Micromass Quattro MS, (Waters, U.K.) equipped with an ESI interface and used in positive ion mode. The MS parameters were as follows: desolvation gas flow rate, 850 L h−1; cone gas flow rate, 50 L h−1; capillary voltage, 3.5 kV; cone voltage, 22 V; CE, 15 V; source temperature, +120 °C; desolvation temperature, +350 °C; multiplier voltage, 650 V. All experiments were made in triplicate. Regeneration of the polymer-coated microplate wells was done using 10 mL of MeOH/acetic acid/water (0.9:0.1:1, v/v). In addition, to check the selectivity of binding to the grafted MIPs, compounds with similar structures to atrazine (metribuzine and simazine) were used in binding experiments as analogs.

3. RESULTS AND DISCUSSION Monomer Selection. A computational approach to the selection of functional monomers for the imprinting of atrazine was carried out using our previously established protocols.30,32 Briefly, the process can be described as being carried out in four stages: (i) design of functional monomer database; (ii) design of a molecular model of the template to be screened; (iii) screening using the Leapfrog algorithm; and (iv) refinement of the model using Molecular Mechanics and/or Molecular Dynamics simulations. The structure of the template and its energy-minimized representation are shown in the Supporting Information (Figure S1) along with the calculated binding energies for the 10 monomers showing the strongest binding interactions according to Leapfrog (Table S1, Supporting Information). From these data, the top three monomers (bisacrylamide, NPEDMA, and IA) were chosen, along with methacrylic acid (MAA), which has previously been used in the preparation of MIPs for atrazine and has been shown to be a superior choice for that template over other monomers.15,33,34 The respective monomer−template complexes for bisacrylamide, IA, MAA, and NPEDMA, corresponding to the Leapfrog binding energies, are shown in the Supporting Information (Figures S2−S5, respectively). Refining the pre-polymerization model was carried out by molecular mechanics simulations using multiple copies of the monomer. Simulated annealing allows the stable complexes to emerge, often showing higher than 1:1 stoichiometry. The results of these studies, including monomer/template ratios for bisacrylamide, IA, and MAA complexes with atrazine and the calculated binding energies are given in the Supporting Information, Table S2. Figures S6−S8 (Supporting Information) show the structures of the complexes formed in silico. It is worth noting that both bisacrylamide and itaconic acid are capable of forming 3:1 complexes with atrazine, with correspondingly high binding energies (−147.58 and −129.70 kcal mol−1, respectively), while methacrylic acid only forms a C



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binding toward atrazine when compared with the binding with simazine and metribuzine.

Figure 2. Binding of atrazine, simazine, and metribuzine (200 ng mL−1 in 20% acetonitrile−water) to the MIP- and NIP-grafted polymer library components (prepared at 1:1, monomer/template ratio). MIP1: bisacrylamide. MIP2: MAA. MIP3: NPEDMA. MIP4: IA. Error bars represent ±1 standard deviation (n = 6 × 3).


At 1:1 all four polymer compositions show only moderate imprinting factors and moderate selectivity for atrazine. The extent of atrazine binding to all four MIPs is remarkably similar and the selectivity of atrazine binding with respect to the analogs is also reflected in the trends shown by the MIPs. In the case of polymers prepared using a 2:1 monomer/ template ratio (Figure 3), methacrylic acid (MIP2) and

If we compare imprinting factors, IF (IF = ratio of binding to MIP/binding to NIP) for this set of experiments, we see the trends emerging in Figure 5. These results clearly show high IFs at 2:1 monomer/template ratio for MAA-based polymers (MIP2, IF = 4.75) and at 3:1 for bisacrylamide-based polymers (MIP1, IF = 4.69). The trends for the other polymers in this set are less remarkable and only show moderate improvements at 3:1 over the other compositions. The results would appear to some extent to correlate with those of the modeling study: MAA performs best at its predicted 2:1 ratio, while bisacrylamide almost matches its performance at 3:1. In the case of itaconic acid, the expectations (3:1) were not fulfilled and NPEDMA may not perform well due to the predicted 1:1 stoichiometry. In order to get another view of the results, Figure 6 shows a comparison of the total binding of atrazine to each MIP composition to the “specific” component of binding (by subtraction of binding to the NIP). The comparison shows that MIPs based on bisacrylamide and itaconic acid show the highest specific binding when used at the 3:1 ratio. On the other hand, MAA-MIP showed the highest specific binding at 2:1 monomer/template. Ideally, for monomers showing the highest specific binding at 3:1, polymers with higher monomer/ template ratios should be prepared to get a fuller picture, although the practical advantages of imprinting at very high functional monomer concentrations are probably not too great. On the basis of specific binding, the results (with the exception again of NPEDMA) seem to follow the trend of the modeling data. Considerations of IF and specific vs nonspecific binding only give a snapshot of MIP performance in this case only in one solvent mixture and at one concentration, but similar considerations are often used to compare MIPs, particularly in a screening situation. We should bear in mind that, as recently shown by Baggiani et al.,38 the binding of potential templates to nonimprinted polymers is a good predictor of the performance of MIPs based on the same functional monomer. In other words, high nonspecific binding (to NIP) can go hand-in-hand with a highly selective MIP.


bisacrylamide-based polymers (MIP1) showed the highest binding of atrazine. In the case of MIP2, the binding was very selective for atrazine, with the analogues showing virtually no uptake by the MIP. At this composition, MIP2 also showed high specific binding, as judged by comparison of MIP and NIP. MIP3 and MIP4, on the other hand, showed only marginally higher binding for the template than the corresponding NIPs, although interestingly both MIPs were still more selective for atrazine, certainly in the case of metribuzine, than their nonimprinted counterparts. When a 3:1 monomer/template ratio was used, MIP1 (bisacrylamide) showed the highest atrazine uptake among all the polymers in the library and almost the best selectivity, despite the corresponding NIP showing a preference for binding metribuzine (Figure 4). All MIPs prepared at this monomer/template ratio showed both specific and selective

4. CONCLUSIONS A new method of preparation of methacrylate-based molecularly imprinted polymer (MIPs) as thin films, grafted to the D



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Figure 5. Imprinting factors (IF) for binding of atrazine (IF = ratio of binding to MIPs/binding to NIP) as a function of monomer/template ratio (bis = bisacrylamide).

Figure 6. Comparison of specific binding and MIP binding for MIPs prepared by bisacrylamide (A), methacrylic acid (B), NPEDMA (C), and itaconic acid (D). Error bars for binding to MIP represent ±1 standard deviation (n = 6 × 3); for specific binding (obtained by subtraction), error bars are ±1 × the square root of the sum of the squares of the standard deviations of the two measurements.

prepared with four functional monomers: bisacrylamide, MAA, NPEDMA, and IA at three monomer/template ratios. All MIPs at all monomer/template ratios showed some imprinting effects and selectivity for the template. The highest performance was shown by MAA at 2:1 and bisacrylamide at 3:1, with both polymers also showing excellent selectivity over their structural analogues. Both results were in line with the predictions of stoichiometry given by modeling, although, in the case of MAA, binding energy alone was not necessarily a good predictor of performance, since MAA scored lower than any of the other monomers tested in the Leapfrog table (Table S1, Supporting Information). The 3:1 bisacrylamide-based MIP gave practically the same performance as the 2:1 MAA polymer, a result that clearly indicates the value of the modeling approach, as

wells of microtiter plates coated with a polyaniline-based macro-iniferter was described. The method was used to prepare a small library of MIPs for atrazine and the corresponding NIPs in order to demonstrate the method. While these coated microtiter plates were used here for a screening experiment, the high reproducibility of the method could also lend itself to the preparation of microplates with MIPs or other polymeric coatings for use in assays, including ELISA. As a “test case” binding of atrazine to the library was used to validate the results of a molecular modeling study, aimed at identifying suitable imprinted polymer compositions for imprinting the herbicide. The preparation of MIP libraries as thin films complements existing mini-MIP and bead-forming methods and library synthesis is relatively rapid and reproducible. MIPs were E



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bisacrylamide is usually only considered as a cross-linker rather than as a functional monomer. It should be emphasized that molecular modeling can be used as a guide to monomer selection and stoichiometry, but its limitations should be borne in mind when attempting to use it as a predictive tool.

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ASSOCIATED CONTENT

S Supporting Information *

Results of molecular modeling, including binding energies and the energy-minimized structures of various template-functional monomer complexes. This information is available free of charge via the Internet at http://pubs.acs.org/

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +44 7892706515. Fax +44 1234 758380. E-mail: d. lakshmi.s06@cranfield.ac.uk. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge with gratitude financial support from the International Atomic Agency, the British Council (MA), and the European Commission (FP7 WATERMIM).

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REFERENCES

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