A RATIONAL APPROACH TO MOLECULARLY IMPRINTED POLYMERS DESIGN: EXPERIMENT AND COMPUTATION

Molecular imprinting is a method that allows to generate biomimetic synthetic materials with molecular recognition properties similar to natural receptors in terms of affinity and selectivity¹. For the design of molecularly imprinted polymers (MIPs) there is a wide variety of functional monomers, which allows to adapt these materials to any type of target molecule and to various applications such as separations materials, binding assays, biosensors, bioimaging, etc. Nevertheless, the vast majority of polymer synthesis protocols found in the literature are based on an empirical approach, using trial-and-error, and/or chemical intuition to find the recipe optimising the affinity between monomer and template in the pre-polymerization mixture and hence the recognition properties of the final polymer. Alternatives, such as combinatorial chemistry² and molecular modelling³ have been proposed to rationalise MIP formulations. However, combinatorial screening is not a predictive tool, and it involves in addition laborious experimental verification. Therefore, when dealing with expensive templates and/or screening a large set of monomers, computational approaches appear the most appropriate.

In this work, a rational design study has been carried out to get a better understanding of monomer-template interactions, of the MIP formation and of the recognition mechanisms in MIP-ligand complexes by comparing experimental data with theoretical calculations. Three MIPs will be presented to illustrate our ration design: they are selective to precursors of malodorous compounds⁴, to cancer biomarkers⁵ and to dipicolinic acid⁶. Since monomer-template interactions are considered the driving forces for the selectivity of the final MIP, we have characterised these interactions in silico and experimentally. Spartan DFT calculations were performed on interactions in vacuum and in polar solvent. These in-silico binding energies were confronted to experimental data obtained by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) spectroscopy methods. This approach combining experimental spectroscopic and calorimetric studies with computational chemistry is a powerful tool for better understanding the interaction mecanisms responsible of the monomer-template complex formation and its relation to the selectivity of the final MIP.

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