Oxytocin-Selective Nanogel Antibody Mimics.

Oxytocin imprinted polymer nanoparticles were synthesized by glass bead supported solid phase synthesis, with NMR and molecular dynamics studies used to investigate monomer-template interactions. The nanoparticles were characterized by dynamic light scattering, scanning- and transmission electron microscopy and X-ray photoelectron spectroscopy. Investigation of nanoparticle-template recognition using quartz crystal microbalance-based studies revealed sub-nanomolar affinity, kd ≈ 0.3 ± 0.02 nM (standard error of the mean), comparable to that of commercial polyclonal antibodies, kd ≈ 0.02-0.2 nM.

The Use of Computational Methods for the Development of Molecularly Imprinted Polymers.

Recent years have witnessed a dramatic increase in the use of theoretical and computational approaches in the study and development of molecular imprinting systems. These tools are being used to either improve understanding of the mechanisms underlying the function of molecular imprinting systems or for the design of new systems. Here, we present an overview of the literature describing the application of theoretical and computational techniques to the different stages of the molecular imprinting process (pre-polymerization mixture, polymerization process and ligand-molecularly imprinted polymer rebinding), along with an analysis of trends within and the current status of this aspect of the molecular imprinting field.

Using Molecular Dynamics in the Study of Molecularly Imprinted Polymers.

Molecular dynamics (MD) simulations of prepolymerization mixtures can provide detailed insights concerning the molecular-level mechanisms underlying the performance of molecularly imprinted polymers (MIPs) and can be used for the in silico screening of candidate polymer systems. Here, we describe the use of MD simulations of all-atom, all-component MIP prepolymerization mixtures and procedures for the evaluation of the simulation data using the Amber simulation software suite.

Urea-Based Imprinted Polymer Hosts with Switchable Anion Preference.

The design of artificial oxyanion receptors with switchable ion preference is a challenging goal in host-guest chemistry. We here report on molecularly imprinted polymers (MIPs) with an external phospho-sulpho switch driven by small molecule modifiers. The polymers were prepared by hydrogen bond-mediated imprinting of the mono- or dianions of phenyl phosphonic acid (PPA), phenyl sulfonic acid (PSA), and benzoic acid (BA) using N-3,5-bis-(trifluoromethyl)-phenyl-N-4-vinylphenyl urea (1) as the functional host monomer. The interaction mode between the functional monomer and the monoanions was elucidated by 1H NMR titrations and 1H-1H NMR NOESY supported by molecular dynamic simulation, which confirmed the presence of high-order complexes. PPA imprinted polymers bound PPA with an equilibrium constant Keq = 1.8 × 105 M-1 in acetonitrile (0.1% 1,2,2,6,6-pentamethylpiperidine) and inorganic HPO42- and SO42- with Keq = 2.9 × 103 M-1 and 4.5 × 103 M-1, respectively, in aqueous buffer. Moreover, the chromatographic retentivity of phosphonate versus sulfonate was shown to be completely switched on this polymer when changing from a basic to an acidic modifier. Mechanistic insights into this system were obtained from kinetic investigations and DSC-, MALDI-TOF-MS-, 1H NMR-studies of linear polymers prepared in the presence of template. The results suggest the formation of template induced 1-1 diad repeats in the polymer main chain shedding unique light on the relative contributions of configurational and conformational imprinting.

Non-Ionic Deep Eutectic Liquids: Acetamide-Urea Derived Room Temperature Solvents.

A family of non-ionic deep eutectic liquids has been developed based upon mixtures of solid N-alkyl derivatives of urea and acetamide that in some cases have melting points below room temperature. The eutectic behaviour and physical characteristics of a series of eleven eutectic mixtures are presented, along with a molecular dynamics study-supported hypothesis for the origin of the non-ideal mixing of these substances. Their use as solvents in applications ranging from natural product extraction to organic and polymer synthesis are demonstrated.

In silico screening of molecular imprinting prepolymerization systems: oseltamivir selective polymers through full-system molecular dynamics-based studies.

All-component molecular dynamics studies were used to probe a library of oseltamivir molecularly imprinted polymer prepolymerization mixtures. Polymers included one of five functional monomers (acrylamide, hydroxyethylmethacrylate, methacrylic acid, 2-(triflouromethyl)acrylic acid, 4-vinylpyridine) and one of three porogens (acetonitrile, chloroform, methanol) combined with the crosslinking agent ethylene glycol dimethacrylate and initiator 2,2'-azobis(2-methylpropionitrile). Polymers were characterized by nitrogen gas sorption measurements and SEM, and affinity studies performed using radioligand binding in various media. In agreement with the predictions made from the simulations, polymers prepared in acetonitrile using either methacrylic or trifluoromethacrylic acid demonstrated the highest affinities for oseltamivir. Further, the ensemble of interactions observed in the methanol system provided an explanation for the morphology of polymers prepared in this solvent. The materials developed here offer potential for use in solid-phase extraction or for catalysis. The results illustrate the strength of this in silico strategy as a potential prognostic tool in molecularly imprinted polymer design.

Theoretical and Computational Strategies for the Study of the Molecular Imprinting Process and Polymer Performance.

The development of in silico strategies for the study of the molecular imprinting process and the properties of molecularly imprinted materials has been driven by a growing awareness of the inherent complexity of these systems and even by an increased awareness of the potential of these materials for use in a range of application areas. Here we highlight the development of theoretical and computational strategies that are contributing to an improved understanding of the mechanisms underlying molecularly imprinted material synthesis and performance, and even their rational design.

On the influence of crosslinker on template complexation in molecularly imprinted polymers: a computational study of prepolymerization mixture events with correlations to template-polymer recognition behavior and NMR spectroscopic studies.

Aspects of the molecular-level basis for the function of ethylene glycol dimethacrylate and trimethylolproprane trimethacrylate crosslinked methacrylic acid copolymers molecularly imprinted with (S)-propranolol have been studied using a series of all-component and all-atom molecular dynamics studies of the corresponding prepolymerization systems. The crosslinking agents were observed to contribute to template complexation, and the results were contrasted with previously reported template-recognition behavior of the corresponding polymers. Differences in the extent to which the two crosslinkers interacted with the functional monomer were identified, and correlations were made to polymer-ligand recognition behavior and the results of nuclear magnetic resonance spectroscopic studies studies. This study demonstrates the importance of considering the functional monomer-crosslinker interaction when designing molecularly imprinted polymers, and highlights the often neglected general contribution of crosslinker to determining the nature of molecularly imprinted polymer-template selectivity.

Molecular dynamics approaches to the design and synthesis of PCB targeting molecularly imprinted polymers: interference to monomer-template interactions in imprinting of 1,2,3-trichlorobenzene.

The interactions between each component of the pre-polymerisation mixtures used in the synthesis of molecularly imprinted polymers (MIP) specific for 1,2,3,4,5-pentachlorobenzene (1) and 1,2,3-trichlorobenzene (2) were examined in four molecular dynamics simulations. These simulations revealed that the relative frequency of functional monomer-template (FM-T) interactions was consistent with results obtained by the synthesis and evaluation of the actual MIPs. The higher frequency of 1 interaction with trimethylstyrene (TMS; 54.7%) than 1 interaction with pentafluorostyrene (PFS; 44.7%) correlated with a higher imprinting factor (IF) of 2.1 vs. 1.7 for each functional monomer respectively. The higher frequency of PFS interactions with 2 (29.6%) than TMS interactions with 2 (1.9%) also correlated well with the observed differences in IF (3.7) of 2 MIPs imprinted using PFS as the FM than the IF (2.8) of 2 MIPs imprinted using TMS as the FM. The TMS-1 interaction dominated the molecular simulation due to high interaction energies, but the weaker TMS-2 resulted in low interaction maintenance, and thus lower IF values. Examination of the other pre-polymerisation mixture components revealed that the low levels of TMS-2 interaction was, in part, due to interference caused by the cross linker (CL) ethyleneglycol dimethylacrylate (EGDMA) interactions with TMS. The main reason was, however, attributed to MeOH interactions with TMS in both a hydrogen bond and perpendicular configuration. This positioned a MeOH directly above the π-orbital of all TMS for an average of 63.8% of MD2 creating significant interference to π-π stacking interactions between 2 and TMS. These findings are consistent with the deviation from the 'normal' molecularly imprinted polymer synthesis ratio of 1 : 4 : 20 (T : FM : CL) of 20 : 1 : 29 and 15 : 6 : 29 observed with 2 and TMS and PFS respectively. Our molecular dynamics simulations correctly predicted the high level of interference from other MIP synthesis components. The effect on PFS-1 interaction by MeOH was significantly lower and thus this system was not adversely affected.

How warfarin's structural diversity influences its phospholipid bilayer membrane permeation.

The role of the structural diversity of the widely used anticoagulant drug warfarin on its distribution in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer membranes was investigated using a series of both restrained (umbrella sampling) and unrestrained molecular dynamics simulations. Data collected from unrestrained simulations revealed favorable positions for neutral isomers of warfarin, the open side chain form (OCO), and the cyclic hemiketal (CCO), along the bilayer normal close to the polar headgroup region and even in the relatively distant nonpolar lipid tails. The deprotonated open side chain form (DCO) was found to have lower affinity for the DOPC bilayer membrane relative to the neutral forms, with only a small fraction interacting with the membrane, typically within the polar headgroup region. The conformation of OCO inside the lipid bilayer was found to be stabilized by intramolecular hydrogen bonding thereby mimicking the structure of CCO. Differences in free energies, for positions of OCO and CCO inside the bilayer membrane, as compared to positions in the aqueous phase, were -97 and -146 kJ·mol(-1). Kinetic analysis based on the computed free energy barriers reveal that warfarin will diffuse through the membranes within hours, in agreement with experimental results on warfarin's accumulation in the plasma, thus suggesting a passive diffusion mechanism. We propose that this membrane transport may be an isomerization-driven process where warfarin adapts to the various local molecular environments encountered under its journey through the membrane. Collectively, these results improve our understanding of the influence of warfarin's structural diversity on the drug's distribution and bioavailability, which in turn may provide insights for developing new formulations of this important pharmaceutical to better address its narrow therapeutic window.

An artificial estrogen receptor through combinatorial imprinting.

Polymeric sorbents targeting endocrine-disrupting estrogen active compounds (EAC) were prepared by terpolymer imprinting using 17ß-estradiol (E2) as template. From a group of eight functional monomers representing Brønsted acids, bases, hydrogen-bond donors and acceptors, as well as π-interacting monomers, a terpolymer library that comprises all possible binary combinations of the functional monomers was prepared. Binding tests revealed that imprinted polymers exhibit a markedly higher affinity for E2 compared to nonimprinted polymers (NIPs) or polymers prepared by using single functional monomers. A combination of methacrylic acid (MAA) and p-vinylbenzoic acid offered a particularly promising lead polymer, displaying an imprinting factor of 17 versus 2.4 for a benchmark polymer prepared by using only MAA as functional monomer. The saturation capacities ascribed to imprinted sites were four to five times higher for this polymer compared to previously reported imprinted polymers. NMR titrations and molecular dynamics simulations corroborated these results, indicating an orthogonal preference of the two functional monomers with respect to the E2 3-OH and 17-OH groups. The optimized polymer exhibited a retentivity for EACs that correlates with their inhibitory effect on the natural receptor. By using the optimized molecularly imprinted polymers (MIPs) in a model water-purification system, they were capable of completely removing ppb levels of a small group of EACs from water. This is in contrast to the performance of nonimprinted polymers and well-established sorbents for water purification (e.g., active carbon), which still contained detectable amounts of the compounds after treatment.

Mechanisms underlying molecularly imprinted polymer molecular memory and the role of crosslinker: resolving debate on the nature of template recognition in phenylalanine anilide imprinted polymers.

A series of molecular dynamics simulations of prepolymerization mixtures for phenylalanine anilide imprinted co-(ethylene glycol dimethacrylate-methacrylic acid) molecularly imprinted polymers have been employed to investigate the mechanistic basis for template selective recognition in these systems. This has provided new insights on the mechanisms underlying template recognition, in particular the significant role played by the crosslinking agent. Importantly, the study supports the occurrence of template self-association events that allows us to resolve debate between the two previously proposed models used to explain this system's underlying recognition mechanisms. Moreover, the complexity of the molecular level events underlying template complexation is highlighted by this study, a factor that should be considered in rational molecularly imprinted polymer design, especially with respect to recognition site heterogeneity.

Rational design of biomimetic molecularly imprinted materials: theoretical and computational strategies for guiding nanoscale structured polymer development.

In principle, molecularly imprinted polymer science and technology provides a means for ready access to nano-structured polymeric materials of predetermined selectivity. The versatility of the technique has brought it to the attention of many working with the development of nanomaterials with biological or biomimetic properties for use as therapeutics or in medical devices. Nonetheless, the further evolution of the field necessitates the development of robust predictive tools capable of handling the complexity of molecular imprinting systems. The rapid growth in computer power and software over the past decade has opened new possibilities for simulating aspects of the complex molecular imprinting process. We present here a survey of the current status of the use of in silico-based approaches to aspects of molecular imprinting. Finally, we highlight areas where ongoing and future efforts should yield information critical to our understanding of the underlying mechanisms sufficient to permit the rational design of molecularly imprinted polymers.