Investigating the Effect of Chemical Modifications on the Ribose Sugar Conformation, Watson–Crick Base Pairing, and Intrastrand Stacking Interactions: A Theoretical Approach

Over the last few decades, chemically modified sugars have been incorporated into nucleic acid-based therapeutics to improve their pharmacological potential. Chemical modification can influence the sugar conformation, Watson-Crick hydrogen (W-C) bonding, and nucleobase stacking interactions, which play major roles in the structural integrity and dynamic properties of nucleic acid duplexes. In this study, we categorized 33 uridine (U*) and cytidine (C*) sugar modifications and calculated their sugar conformational parameters. We also calculated the Watson-Crick hydrogen bond energies of the modified RNA-type base pairs (U*:A and C*:G) using DFT and sSAPT0 methods. The W-C base pairing energy calculations suggested that the <i>South</i>-type modified sugar strengthens the C*:G base pair and weakens the U*:A base pair compared to the unmodified one. In contrast, the <i>North</i>-type sugar modifications form weaker C*:G base pair and marginally stronger U*:A base pair compared to the <i>South</i>-type modified sugars. Moreover, intrastrand base stacking energies were calculated for 15 modifications incorporated at the fourth position in 7-mer non-self-complementary RNA duplexes [(GCAU*GAC)₂ and (GCAC*GAC)₂], utilizing molecular dynamics simulation and quantum mechanical (DFT and sSAPT0) methods. The sugar modifications were found to have minimal effect on the intrastrand base-stacking interactions. However, the glycol nucleic acid modification disturbs the intrastrand base-stacking significantly, corroborating the experimental data.