Mechanistic Insights into the Stabilizing Role of Deep Eutectic Solvents for Nucleic Acids: An <i>In Silico</i> Analysis

The cold chain system poses a significant obstacle to equitable global access to safe and effective nucleic acid-based vaccines. There is, therefore, a critical need to eliminate or improve this vaccine coverage gap by minimizing the costly and labor-intensive cold chain process, thereby providing equitable access to these life-saving therapeutics. In this work, quantum chemical evaluation qualitatively compared the interactions of a choline chloride/trehalose-based deep eutectic solvent (DES) with model bases (adenine (A), guanine (G), cytosine (C), thiamine (T), and uracil (U)) and their base pairs AT, AU, and GC in nucleic acids. We found that unpaired purines primarily interacted with the DES through C-H···π and hydrogen bonding, leading to cage-like structures, while pyrimidines primarily engaged through hydrogen bonding. In DES/base pair complexes, the AT base pair weakened and partially lost planarity due to C-H···π interactions, while the AU base pair was disrupted by additional hydrogen bonding with Cl^-. Conversely, the GC base pair retained its structure with strengthened hydrogen bonding in the presence of DES. Aromaticity increased in unpaired bases and base pairs AT and AU due to multiple hydrogen bonds but decreased in the DES/GC complex dominated by C-H···π interactions. Charge transfer analysis showed that purines lost electron density upon interacting with DES, while pyrimidines gained electron density. Interestingly, the GC and AT base pairs that retained pairing lost electron density to DES, whereas the AU base pair gained electron density, indicating complex interactions. The thermochemistry indicated favorable interactions of DES with unpaired bases and base pairs. However, it also suggests that once the bases are unpaired, it is energetically expensive for them to pair again.