LAUSR

Because of their strong electron-rich properties, nucleic acids (NAs) can theoretically serve as halogen bond (XB) acceptors. From a PDB database survey, Kolář found that no XBs are formed between noncovalent ligands and NAs. Through statistical database analysis, quantum-mechanics/molecular-mechanics (QM/MM) optimizations, and energy calculations, we find that XBs formed between natural NAs and noncovalent ligands are primarily underestimated and that NAs can serve as XB acceptors to interact with noncovalent halogen ligands. Finally, through energy calculations, natural bond orbital analysis, and noncovalent interaction analysis, XBs are confirmed in 13 systems, among which two systems (445D and 4Q9Q) have relatively strong XBs. In addition, on the basis of energy scanning of four model systems, we explore the geometric rule for XB formation in NAs. This work will inspire researchers to utilize XBs in rational drug design targeting NAs.