Decoding the enigma of RNA-protein recognition: quantum chemical insights into arginine fork motifs

Arginine (Arg) forks are noncovalent recognition motifs wherein an Arg interacts with the phosphates and guanine nucleobases of RNA, providing extraordinary specific RNA:protein recognition. In this work, we carried out an in-depth DFT based quantum mechanical investigation on all known classes of Arg forks to estimate their intrinsic structural stabilities and interaction energies. The optimized structures closely mimic the structural characteristics of Arg forks and this close match between experimental and optimized geometries suggests that Arg forks are intrinsically stable and do not require additional support from other RNA or protein components. Both hydrogen-bonding and cation-π interactions are important for the intrinsic stability of Arg forks, providing an average interaction energy of -36.7 kcal mol^-1. Furthermore, we found a direct correlation between Arg forks' interaction energies and the number of phosphates involved, which is more delicately modulated by other factors, like the types of hydrogen bonds and cation-π interactions that constitute the Arg fork. Additionally, we observed a positive correlation between the average interaction energies of Arg forks and the frequency of their occurrence in available crystal structures. At the broader level, this work establishes the groundwork for more precise modeling and understanding of RNA-protein interfaces, which could have potential implications in advancing the knowledge of biomolecular recognition patterns.