Quantum mechanical investigation of the nature of nucleobase-urea stacking interaction, a crucial driving force in RNA unfolding in aqueous urea

Abstract

Urea-assisted denaturation of protein and RNA has been shown to be a valuable tool to study their stabilities and folding phenomena. It has been shown that stacking interactions between nucleobases and urea are one of the driving forces of denaturation. In this study, the ability of urea to form unconventional stacking interactions with RNA bases is investigated by performing high-level quantum calculations (RI-MP2/aug-cc-pVDZ level) on a few thousands of model systems. Four systems were considered based on the RNA nucleobases (GUA, ADE, CYT, and URA) for the investigation. For each system, a set of models were designed to study the role of hetero-atoms/groups of the nucleobases on stacking interactions with urea moiety with respect to every possible pair. Several plane-parallel complexes were generated with urea on top of aromatic systems to exhaustively study all possible factors for urea-nucleobases stacking interactions. Energy decomposition analysis (EDA), atoms in molecules (AIM) and natural bond orbital (NBO) analysis were performed to gain better insights on non-covalent stacking interactions. Dispersion component was found to be heavily stabilizing, while the $$\hbox {E}_\mathrm{HF}$$ was found to be repulsive for all the four systems indicating lack of hydrogen bonding (HB) type interactions and presence of dispersion type interactions. Amide and carbonyl groups of urea molecule were found to play a major role in favourable stacking interactions. We demonstrate that along with functional groups present on the nucleobases, the orientation of urea molecules plays a vital role in stabilizing the urea-nucleobase non-covalent interactions. The proposed study quantifies and provides a comprehensive theoretical description of urea nucleobase unconventional stacking interactions which helps to unravel urea driven RNA unfolding mechanism. SYNOPSIS Position and orientation effects on the stacking interactions between the urea and nucleobases, the driving force in urea-induced RNA denaturation, were studied using quantum mechanical calculations. Dispersion effects, functional groups of the bases and orientation of urea molecules are the key contributing factors affecting these interactions.