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.

Polymeric sorbents targeting endocrine-disrupting estrogen active compounds (EAC) were prepared by terpolymer imprinting using 17 beta-estradiol (E2) as template. From a group of eight functional monomers representing Bronsted acids, bases, hydrogen-bond donors and acceptors, as well as pi-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.

In this study, computational methods were employed in efforts to elucidate physical mechanisms underlying the ligand selectivity of polymeric sorbents produced through the molecular imprinting of 17-beta-estradiol. Previous computational and experimental studies had identified candidate systems applicable to the development of synthetic polymeric receptors for the detection and possible removal of pollutants with endocrine-disrupting properties. Here we present a series of comprehensive molecular dynamics studies of candidate molecular imprinting prepolymerization systems. The results from the studies highlight the role of the cross-linker and the importance of the interplay between functionalities of the various monomers employed in template complexation. The significance of these results for future studies is discussed.

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.