A computational approach to studying monomer selectivity towards the template in an imprinted polymer

A computational approach was proposed to study monomer–template interactions in a molecularly imprinted polymer (MIP) in order to gain insight at the molecular level into imprinting polymer selectivity, regarding complex formation between template and monomer at the pre-polymerisation step. This is the most important step in MIP preparation. In the present work, chlorphenamine (CPA), diphenhydramine (DHA) and methacrylic acid (MAA), were chosen as the template, non-template, and monomer, respectively. The attained complexes were optimised, and changes in the interaction energies, atomic charges, IR spectroscopy results, dipole moment, and polarisability were studied. The effects of solvent on template–monomer interactions were also investigated. According to a survey of the literature, this is the first work in which dipole moment and polarisability were used to predict the types of interactions existing in pre-polymerisation complexes. In addition, the density functional tight-binding (DFTB) method, an approximate version of the density functional theory (DFT) method that was extended to cover the London dispersion energy, was used to calculate the interaction energy.     

Combinatorial screening of polymer precursors for preparation of benzo[α] pyrene imprinted polymer: an ab initio computational approach

A combinatorial screening procedure was used for the selection of polymer precursors in the preparation of molecularly imprinted polymer (MIP), which is useful in the detection of the air pollution marker molecule benzo[a]pyrene (BAP). Molecular imprinting is a technique for the preparation of polymer materials with specific molecular recognition receptors. The preparation of imprinted polymers requires polymer precursors such as functional monomer, cross-linking monomer, solvent, an initiator of polymerization and thermal or UV radiation. A virtual library of functional monomers was prepared based on interaction binding scores computed using HyperChem Release 8.0 software. Initially, the possible minimum energy conformation of the monomers and BAP were optimized using the semi-empirical (PM3) quantum method. The binding energy between the functional monomer and the template (BAP) was computed using the Hartree-Fock (HF) method with 6-31 G basis set, which is an ab initio approach based on Moller-Plesset second order perturbation theory (MP2). From the computations, methacrylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) were selected for preparation of BAP imprinted polymer. The larger interaction energy (ΔE) represents possibility of more affinity binding sites formation in the polymer, which provides high binding capacity. The theoretical predictions were complimented through adsorption experiments. There is a good agreement between experimental binding results and theoretical computations, which provides further evidence of the validity of the usefulness of computational screening procedures in the selection of appropriate MIP precursors in an experiment-free way.     

Protein-responsive imprinted polymers with specific shrinking and rebinding

Stimuli-responsive protein imprinted polymers were obtained via a combination of molecular imprinting and reversible stimuli-responsive polymer using lysozyme or cytochrome c as template, N-isopropylacrylamide (NIPA) as major monomer, methacrylic acid (MAA) and acrylamide (AAm) as functional co-monomers, and N,N-methylenebisacrylamide (MBAAm) as crosslinker. The molecularly imprinted polymers (MIPs) can respond not only to external stimuli such as temperature and salt concentration, but also to the corresponding template protein with significant specific volume shrinking. This specific shrinking behavior was attributed to the synergistic effect of multiple-site weak interactions (electrostatic force, hydrogen bonding and hydrophobic interaction) and the cavity effect. The MIPs showed highly selective adsorption of template proteins with specific shrinking compared with the non-imprinted polymers. The results indicated that the MIPs seemed to change shape to accommodate the conformation of the template protein leading to the formation of a shape complementary cavity.     

Density functional theory study on the interaction between keto-9H guanine and aspartic acid

A theoretical study was performed using density functional theory (DFT) to investigate hydrogen bonding interactions in signature complexes formed between keto-9H guanine (Gua) and aspartic acid (Asp) at neutral pH. Optimized geometries, binding energies and the theoretical IR spectra of guanine, aspartic acid and their corresponding complexes (Gua-Asp) were calculated using the B3LYP method and the 6-31+G(d) basis set. Stationary points found to be at local minima on the potential energy surface were verified by second derivative harmonic vibrational frequency calculations at the same level of theory. AIM theory was used to analyze the hydrogen bonding characteristics of these DNA base complex systems. Our results show that the binding motif for the most stable complex is strikingly similar to a Watson-Crick motif observed in the guanine-cytosine base pair. We have found a range of hydrogen bonding interactions between guanine and aspartic acid in the six complexes. This was further verified by theoretical IR spectra of ω(C-H---O-H) cm⁻¹ stretches for the Gua-Asp complexes. The electron density plot indicates strong hydrogen bonding as shown by the 2p _z dominant HOMO orbital character.     

Rational synthesis of pindolol imprinted polymer by non-covalent protocol based on computational approach

Pindolol (PDL) is a potent and specific adrenoreceptor blocking agent. It is widely used in the treatment of hypertension, cardiac arrhythmia and angina pectoris. Molecularly imprinted polymers (MIPs) are synthetic receptors having potential applications in drug delivery systems and devices such as diagnostic sensors. In the present work, ab initio quantum mechanical simulations and computational screening were used to identify functional monomer having best interactions with PDL. A virtual library of 16 functional monomers was built and the possible minimum energy conformation of the monomers and PDL were calculated using Hartree-Fock (HF) method for the synthesis of PDL imprinted polymer. The interaction energy between functional monomer and the template were corrected by means of basis set superposition error (BSSE) in all pre-polymerization complexes. The hydrogen bonding between PDL and functional monomer was evaluated by changes in bond lengths before and after complex formation. The virtual template-monomer complex with highest interaction energy is more stable during the polymerization and leads to high selectivity and specificity toward the template. The interaction energy of PDL was found to be the highest with itaconic acid followed by 4-vinyl pyridine and least with acrylonitrile. Taking a spectroscopic viewpoint, results obtained from analysis of the harmonic infrared spectrum were examined. Red and blue shifts related to the stretching frequencies of either donors or acceptors of protons were identified and compared experimentally. Stoichiometric mole ratio of template to functional monomer was optimized and confirmed by UV visible spectra titrations. The theoretical results were correlated by evaluation of binding parameters of MIPs. The experimental binding results were in good agreement with theoretical computations.     

Virtual imprinting as a tool to design efficient MIPs for photosynthesis-inhibiting herbicides

Molecular modelling and computational screening were used to identify functional monomers capable of interacting with several different photosynthesis-inhibiting herbicides. The process involved the design of a virtual library of molecular models of functional monomers containing polymerizable residues and residues able to interact with the template through electrostatic, hydrophobic, Van der Waals forces and dipole-dipole interactions. Each of the entries in the virtual library was probed for its possible interactions with molecular models of the template molecules. It was anticipated that the monomers giving the highest binding score would represent good candidates for the preparation of affinity polymers. Strong interactions were computationally determined between acidic functional monomers like methacrylic acid (MAA) or itaconic acid (IA) with triazines, and between vinylimidazole with bentazone and bromoxynil. Nevertheless, weaker interactions were seen with phenylureas. The corresponding blank polymers were prepared using the selected monomers and tested in the solid phase extraction (SPE) of herbicides from chloroform solutions. A good correlation was found between the binding score of the monomers and the affinities of the corresponding polymers. The use of computationally designed blanks can potentially eliminate the need for molecular imprinting, (adding a template to the monomer mixture to create specific binding sites). Data also showed that some monomers have a natural selectivity for some herbicides, which can be further enhanced by imprinting. Thus, in regard to retention on the blank polymer, we can estimate if the resulting imprinted polymer will be effective or not.     

Theoretical research on cage-like furazan-based energetic compounds and its derivatives

In this paper, a novel molecularly imprinted polymer (MIP) for specific adsorption of steviol glycosides was designed, and the imprinting mechanism of self-assembly system between template and monomers was clearly explored. Firstly, steviol (STE) was chosen as dummy template, and the density functional theory (DFT) at B3LYP/6–31 + G (d, p) level was used to select monomers, imprinting molar ratios, solvents, and cross-linking agents. The selectivity to five steviol glycosides was also calculated. Importantly, reduced density gradient (RDG) theory combined with atom in molecules (AIM) and infrared spectrum (IR) was applied to investigate the bonding situation and the nature of noncovalent interaction in self-assembly system. The theoretical designed results showed that the template which interacts with acrylic acid (AA) has the minimum binding energy, and the complex with the molar ratio of 1 : 4 has the most stable structure. Toluene (TL) and ethylene glycol dimethacrylate (EGDMA) were chosen as the optimal solvent and cross-linking agent, respectively. Five hydrogen bonds formed in the self-assembly system are the key forces at the adsorption sites of MIPs through the RDG and AIM analyses. The MIPs were synthesized by theoretical predictions, and the results showed that the maximum adsorption capacity towards dulcoside A is 26.17 mg/g. This work provided a theoretical direction and experimental validation for deeper researches of the MIPs for steviol glycosides. In addition, the method of RDG theory coupled with AIM and IR also could be used to analyze other imprinting formation mechanisms systematically.

     

Excited state intermolecular hydrogen bond’s effect on the luminescent behaviour of the 2D covalent organic framework (PPy-COF): A TDDFT insight

The theoretical investigation of electronically excited stated intermolecular hydrogen bonding dynamics of the 2D luminescent polypyrene covalent organic framework and methanol molecule (PPy-COF-MeOH) was performed using the density functional theory (DFT) and time-dependent (TD-DFT) method. The strengthening of Hydrogen bonds C-H---O-H and B-O---H-O upon photoexcitation was confirmed via comparison of geometric structures, electronic transition energies, ¹H-NMR, binding energies, UV-Vis and infrared spectra in S0 and S1 states. Frontier molecular orbitals (MOs) analysis, electronic configuration, Mulliken charge analysis; and the charge density variation in hydrogen bonding proximity demonstrated that the strengthened hydrogen bonds facilitate the nonradiative path which may consequently proceed the luminescence quenching. Hence, the molecular material property prediction package (MOMAP) programme verified the fluorescence quenching because PPy-COF-MeOH complex showed a lower fluorescent rate constant compared to isolated PPy-COF fragment. The S1-T1 energy gap analysis also revealed the possibility of the Intersystem crossing (ISC). Above results significantly highlighted the role of the hydrogen bonding dynamics on luminescence property of the PPy-COF.     

A computational approach to study functional monomer‐protein molecular interactions to optimize protein molecular imprinting

Molecular imprinting has become a promising approach for synthesis of polymeric materials having binding sites with a predetermined selectivity for a given analyte, the so‐called molecularly imprinted polymers (MIPs), which can be used as artificial receptors in various application fields. Realization of binding sites in a MIP involves the formation of prepolymerization complexes between a template molecule and monomers, their subsequent polymerization, and the removal of the template. It is believed that the strength of the monomer‐template interactions in the prepolymerization mixture influences directly on the quality of the binding sites in a MIP and consequently on its performance. In this study, a computational approach allowing the rational selection of an appropriate monomer for building a MIP capable of selectively rebinding macromolecular analytes has been developed. Molecular docking combined with quantum chemical calculations was used for modeling and comparing molecular interactions among a model macromolecular template, immunoglobulin G (IgG), and 1 of 3 electropolymerizable functional monomers: m‐phenylenediamine (mPD), dopamine, and 3,4‐ethylenedioxythiophene, as well as to predict the probable arrangement of multiple monomers around the protein. It was revealed that mPD was arranged more uniformly around IgG participating in multiple H‐bond interactions with its polar residues and, therefore, could be considered as more advantageous for synthesis of a MIP for IgG recognition (IgG‐MIP). These theoretical predictions were verified by the experimental results and found to be in good agreement showing higher binding affinity of the mPD‐based IgG‐MIP toward IgG as compared with the IgG‐MIPs generated from the other 2 monomers.     

Screening of different computational models for the preparation of sol–gel imprinted materials

Different computational models were used and screened to find a rational way in selecting the appropriate functional silane monomer for the best molecular imprinted xerogel (MIX) formulation. Several functional silane monomers were used and allowed to react with a template model, tetracycline (TC). The resulting template-monomer complex molecules were first optimized and their interaction energies (IEs) were calculated using different computational methods such as semi-empirical methods, ab-initio methods, density functional theory (DFT) methods and solvent model method. The formulations used for calculation were also prepared and their performance in binding with TC was determined using tritium labeled sample. Results showed that the rankings of the different formulations varied with the different computational methods. However, rankings of the IEs of the xerogels are similar to that of the imprinting factor (IF) when HF and B3LYP at SV(P) and SVP basis set levels were used. The best imprinted xerogel, allyltriethoxysilane (AtEOS) ranked first in ten out of the 26 computational models that were screened and at all computational methods at tetramer system.     

Detailed positron annihilation lifetime spectroscopic investigation of atrazine imprinted polymers grafted onto PE/PP non‐woven fabrics

This study presents the preparation of molecularly imprinted matrices by using radiation‐induced grafting technique onto polyethylene/polypropylene (PE/PP) non‐woven fabrics. Atrazine imprinted polymers were grafted onto PE/PP non‐woven fabrics through the use of methacrylic acid (MAA) and ethylene glycol dimethylacrylate (EGDMA) as the functional monomer and crosslinking agent, respectively. Grafted MIPs were characterized by attenuated total reflectance Fourier transform infra‐red spectroscopy (ATR‐FTIR), X‐ray photoelectron spectroscopy (XPS), elemental analysis, scanning electron microscopy (SEM), and positron annihilation lifetime spectroscopy (PALS). The average diameter of free volume holes was determined as 0.612 nm which correlates very well with the size of template molecule atrazine, 0.512 nm. Binding behaviors were investigated against various factors, such as concentration of template molecule, pH, and contact time. Furthermore, the specific selectivity of grafted MIP on non‐woven fabric was studied by using other common triazine compounds, such as simazine and metribuzine which show structural similarities to atrazine. The specific binding values for atrazine, simazine, and metribuzine were determined as 40%, 2.5%, and 1.5%, respectively.     

Effects of solvent polarity on the absorption and fluorescence spectra of chlorogenic acid and caffeic acid compounds: determination of the dipole moments

The effects of solvent polarity on absorption and fluorescence spectra of biologically active compounds (chlorogenic acid (CGA) and caffeic acids (CA)) have been investigated. In both spectra pronounced solvatochromic effects were observed with shift of emission peaks larger than the corresponding UV‐vis electronic absorption spectra. From solvatochromic theory the ground and excited‐state dipole moments were determined experimentally and theoretically. The differences between the excited and ground state dipole moment determined by Bakhshiev, Kawski–Chamma–Viallet and Reichardt equations are quite similar. The ground and excited‐state dipole moments were determined by theoretical quantum chemical calculation using density function theory (DFT) method (Gaussian 09) and were also similar to the experimental results. The HOMO‐LUMO energy band gaps for CGA and CFA were calculated and found to be 4.1119 and 1.8732 eV respectively. The results also indicated the CGA molecule is more stable than that of CFA. It was also observed that in both compounds the excited state possesses a higher dipole moment than that of the ground state. This confirms that the excited state of the hydroxycinnamic compounds is more polarized than that of the ground state and therefore is more sensitive to the solvent. Copyright © 2015 John Wiley & Sons, Ltd.     

Novel enantioselective fluorescent sensors for tartrate anion based on acridinezswsxa

Novel chiral fluorescence sensors L‐1 and D‐1 incorporating N‐Boc‐protected alanine and acridine moieties were synthesized. The recognition ability of the sensors was studied by fluorescence titration, ¹H NMR spectroscopy and density functional theory (DFT) calculations. The sensors exhibited good enantioselective fluorescent sensing ability toward enantiomers of tartrate anion for the selected carboxylate anions and formed 1: 1 complexes by multiple hydrogen bonding interactions.     

Synthesis of a molecularly imprinted polymer for the solid‐phase extraction of betulin and betulinic acid from plane bark

Introduction – Plant extracts are usually complex mixtures of various polarity compounds and their study often includes a purification step, such as solid‐phase extraction (SPE), to isolate interest compounds prior analytical investigations. Molecularly imprinted polymers (MIPs) are a new promising type of SPE material which offer tailor‐made selectivity for the extraction of trace active components in complex matrices. Numerous specific cavities that are sterically and chemically complementary of the target molecules, are formed in imprinted polymers. A molecularly imprinted polymer (MIP) was synthesised in order to trap a specific class of triterpene, including betulin and betulinic acid from a methanolic extract of plane bark. Methodology – Imprinted polymers were synthesised by thermal polymerisation of betulin as template, methacrylic acid (MAA) or acrylamide (AA) as functional monomer, ethylene glycol dimethacrylate as crosslinking agent and chloroform as porogen. Afterwards, MAA‐ and AA‐MIPs were compared with their non‐imprinted polymers (NIPs) in order to assess the selectivity vs betulin and its derivatives. Recovered triterpenes were analysed by HPLC during MIP‐SPE protocol. Results – After SPE optimisation, the MAA‐imprinted polymer exhibited highest selectivity and recovery (better than 70%) for betulin and best affinity for its structural analogues. Thus, a selective washing step (chloroform, acetonitrile) removed unwanted matrix compounds (fatty acids) from the SPE cartridge. The elution solvent was methanol. Finally, the MAA‐MIP was applied to fractionate a plane bark methanolic extract containing betulin and betulinic acid. Conclusion – This study demonstrated the possibility of direct extraction of betulin and its structural analogues from plant extracts by MIP technology. Copyright © 2009 John Wiley & Sons, Ltd.     

Catalytic amidolysis of amino acid p-nitroanilides using transition state analogue imprinted artificial enzymes: Cooperative effect of pyridine moiety

Enzyme-like polymer catalysts with the imprints of phosphonate transition state analogue (TSA) lined along with imidazole and pyridine moieties were synthesized using methacryloyl-l-histidine and 4-vinylpyridine as the functional monomers and phenyl-1-(N-benzyloxycarbonylamino)-2-(phenyl)ethyl phosphonate – the TSA of hydrolytic reaction as the template for the amidolysis of N-benzyloxycarbonyl-l-phenylalanine p-nitroanilide (Z-l-Phe-PNA). Polymers containing different functional groups can act together to provide catalytic activity and selectivity superior to what can be obtained from monofunctional analogues. The higher rate acceleration exhibited by the bifunctional polymer over the monofunctional polymers indicates cooperative catalysis of imidazole and pyridine moieties. The optimum catalytic competence is shown by the bifunctional polymer containing imidazole and pyridine moieties in 2:1 M ratio which may be due to alignment of the functional groups in proper H-bond distance. In addition to the non-covalent interactions like hydrogen bonding or π-stacking interactions between the functional groups of the polymer and the template, 3D-microcavities complementary to the geometry of the template are necessary for effective shape selective binding. Michaelis-Menten kinetics implies that only the catalysts with imidazole moieties act as enzyme-like catalysts and imidazole is the key catalytic function of the enzyme mimics.     

Theoretical study of the triangular bonding complex formed by carbon tetrabromide, a halide, and a solvent molecule in the gas phase

MP2(full)/aug-cc-pVDZ(-PP) computations predict that new triangular bonding complexes (where X^? is a halide and H–C refers to a protic solvent molecule) consist of one halogen bond and two hydrogen bonds in the gas phase. Carbon tetrabromide acts as the donor in the halogen bond, while it acts as an acceptor in the hydrogen bond. The halide (which commonly acts as an acceptor) can interact with both carbon tetrabromide and solvent molecule (CH₃CN, CH₂Cl₂, CHCl₃) to form a halogen bond and a hydrogen bond, respectively. The strength of the halogen bond obeys the order CBr₄???Cl^? > CBr₄???Br^? > CBr₄???I^?. For the hydrogen bonds formed between various halides and the same solvent molecule, the strength of the hydrogen bond obeys the order C-H???Cl^? > C-H???Br^? > C-H???I^?. For the hydrogen bonds formed between the same halide and various solvent molecules, the interaction strength is proportional to the acidity of the hydrogen in the solvent molecule. The diminutive effect is present between the hydrogen bonds and the halogen bond in chlorine and bromine triangular bonding complexes. Complexes containing iodide ion show weak cooperative effects.

Capacitive sensor for environmental monitoring based on thin films of molecularly imprinted polymers. Computer modeling for optimization of the composition of synthetic analogs of bioreceptors

A capacitive sensor for environmental monitoring based on thin films of desmetryn-selective molecularly imprinted polymer (MIP) was developed. The method of modification of gold electrodes with the thin film of herbicide-selective MIP using the grafting polymerization approach was developed. The method of computational modeling was used to optimize the composition of desmetryn-selective MIPs. It was shown that 2-acrylamido-2-methyl-1-propan-sulfonic acid is the optimal functional monomer for desmetryn. Formation of synthetic binding sites in MIPs was demonstrated to be determined by the binding energy between the template and functional monomers as well as the number of functional groups taking part in the recognition of the template molecule. Electrochemical processes occurring at the MIP-modified electrode were analyzed. The detection limit for desmetryn comprised 100 nM. High selectivity of the capacitive sensor towards structural analogues of desmetryn as well as high operational and storage stabilities was demonstrated.     

Validation of computational approach to study monomer selectivity toward the template Gallic acid for rational molecularly imprinted polymer design

Gallic acid (GA) is important for pharmaceutical industries as an antioxidant. It also finds use in tanning, ink dyes and manufacturing of paper. Molecularly imprinted polymers (MIP), which are tailor made materials, can play an excellent role in separation of GA from complex matrices. Molecular recognition being the most important property of MIP, the present work proposes a methodology based on density functional theory (DFT) calculations for selection of suitable functional monomer for a rational design of MIP with a high binding capacity for GA. A virtual library of 18 functional monomers was created and screened for the template GA. The prepolymerization template-monomer complexes were optimized at B3LYP/6-31G(d) model chemistry and the changes in the Gibbs free energy (ΔG) due to complex formation were determined on the optimized structures. The monomer with the highest Gibbs free energy gain forms most stable complex with the template resulting in formation of more selective binding sites in the polymeric matrix in MIPs. This can lead to high binding capacity of MIP for GA. Amongst the 18 monomers, acrylic acid (AA) and acrylamide (AAm) gave the highest value of ΔG due to complex formation with GA. 4-vinyl pyridine (4-Vp) had intermediate value of ΔG while, methyl methacrylate (MMA) gave least value of ΔG due to complex formation with GA. Based on this study, the MIPs were synthesized and rebinding performance was evaluated using Langmuir-Freundlich model. The imprinting factor for AA and AAm based MIPs were 5.28 and 4.80 respectively, 4-Vp based MIP had imprinting factor of 2.59 while MMA based MIP exhibited an imprinting factor of 1.95. The experimental results were in good agreement with the computational predictions. The experimental data validated the DFT based computational approach.     

Chiral separation using molecularly imprinted heteroaromatic polymers

Novel molecularly imprinted polymer systems utilizing 4-vinylpyridine and 1-vinylimidazole as functional monomers have been developed for enantioselective recognition of carboxylic and N-protected amino acids. Non-covalent interactions between the functional monomers and the template molecules were the source of the subsequent recognition sites in the resultant polymers. The capacity of the polymers for molecular recognition was investigated by using them as stationary phases in the HPLC mode. Polymers prepared with 4-vinylpyridine were found to be more efficient in racemic resolution than those prepared with 1-vinylimidazole. When applying a racemic mixture of the template molecule, the polymers showed highest affinity for the enantiomer used as template. Imprints of a racemic template molecule, as expected, did not exhibit enantioselectivity. The optimal molar ratio of 4-vinylpyridine to the template Cbz-L -Asp-OH in the polymerization mixture was determined to be 12:1. In addition to enantioselectivity, the investigated polymers demonstrated ‘ligand selectivity’ e.g., a Cbz-L -Asp-OH-imprinted polymer was able to separate Cbz-D ,L -Asp-OH, but was unable to separate Cbz-D ,L -Glu-OH.     

Structure,energetics and properties of some molecules with potent anti-HIV activity: a theoretical study

Density functional theory (DFT; B3LYP) and Hartree–Fock (HF; 3-21G, 6-31G(d) and 6-311G(d,p)) calculations with complete geometry optimisations are carried out in the ground state on five 6-aminoquinolone derivatives, which have been proved to be highly effective in inhibiting HIV replication, to study their structures, energetics and HOMO–LUMO correlation with physiological action. The gas-phase calculations and single-point polarisable continuum model water-phase calculations show that the molecules are highly effective in inhibiting HIV replication, which is in excellent agreement with the experiment. Structural features, energies, charge densities and HOMO–LUMO correlation have been found to substantiate the experimental findings. Compound 4 (pyrazine) shows some special features in DFT calculations which are not found in HF calculations. In the present series, HF results are more reliable as expected.