Theoretical insights into the compatibility of template-monomer-crosslinker-solvent for cortisol molecularly imprinted polymer pre-polymerization†

Detection of cortisol (Cort), a stress hormone, is essential in monitoring chronic and mental health stress. As such, there is growing interest in the development of cortisol molecularly imprinted polymers (MIPs) as molecular receptors for sensor development. Of the cortisol MIPs described in the literature, the optimization of the functional monomers has been through trial-and-error experimentation. Through a computational approach, the number of optimization experiments can be reduced, which is time efficient and cost effective, while reducing chemical wastage. In addition to density functional theory (DFT) calculations, this study used an atomistic molecular dynamics simulation approach that resembles that of the real-life experimental methods to elucidate the compatibility of template-monomer-crosslinkers-solvent for cortisol MIP receptors that can efficiently recognize and capture cortisol from biological fluids. The functional monomer investigated were 4-vinylpyridine (4VP), acrylic acid (AA), acrylamide (AM), glycidyl methacrylate (GMA), 2-hydroxyethyl methacrylate (HEMA) and methylacrylic acid (MAA) with ethylene glycol dimethacrylate (EGDMA) as the crosslinker. The intermolecular hydrogen bonds and the template-monomer binding energies obtained through DFT suggested Cort-MAA as the most stable complex both in the gas phase and solution. Considering the calculated solvent energies, acetonitrile was recommended as a porogenic solvent. Through molecular dynamics simulation, various parameters were analyzed to explain the compatibility of the functional monomer with the cortisol template in the MIP development. From blend analysis of template-monomer, Cort-4VP was found to be the most miscible complex. For template-monomer-crosslinker (EGDMA), the mean square displacement (MSD) and diffusion coefficient analyses indicated 1 : 2 (cortisol/monomer) as the ratio in which the complexes are most stable. The highest peaks observed from the Radial distribution function were for Cort-MAA and Cort-AA at 1 : 4 indicating better interactions of the functional monomers with the Cort. Investigating the effect of solvents for template-monomer-crosslinker-solvent, the lowest MSD was at 1 : 4 with three complexes having the lowest values for solubility parameters at 1 : 4 confirming this ratio to be generally suitable for the composition of cortisol MIPs pre-polymerization.