Rationalization of molecular interactions in template-functional monomer pre-polymerization complexes

Molecular imprinting, an advanced technique for synthesizing polymer matrices with specific recognition sites, emulates the natural recognition processes found in biological receptors. This study investigates the molecular imprinting of three hazardous food contaminants: Aflatoxin B1, Glyphosate, and Sulfamethoxazole, using 28 functional monomers. Employing the semi-empirical global optimization CREST approach combined with DFT, the research aims to identify the most stable pre-polymerization complex conformations and accurately calculate stabilization energies. The results indicate that functional monomers with multiple carboxylic or hydroxyl groups, such as itaconic acid and dopamine, exhibit superior efficacy due to their capacity to form robust hydrogen bond interactions with the template molecules. In contrast, 4-ethylstyrene, which lacks the necessary functional groups for strong interactions, showed the lowest interaction tendency. Notably, the employed clustering approach effectively separated the investigated monomers into distinct groups based on their stabilization energies, which correlates well with their chemical structure. Non-covalent interactions of each cluster representative were visualized, providing a more detailed insight into the main factors contributing to the interaction energy. The theoretical CREST/DFT ensemble approach, demonstrated herein, has proven to be a fast and reliable method for locating the most stable pre-polymerization complexes and accurately determining energy and non-covalent interactions. Consequently, this approach can be utilized to predict optimal imprinting, particularly when rapid screening of a large number of templates and monomers is required. The findings advance molecular imprinting technology, enhancing its applications in biosensors, drug delivery, and environmental monitoring, and pave the way for developing highly selective and efficient synthetic receptors.