Atomistic Investigation of the Effect of Incremental Modification of Deoxyribose Sugars by Locked Nucleic Acid (β-D-LNA and α-L-LNA) Moieties on the Structures and Thermodynamics of DNA-RNA Hybrid Duplexes

Chemically modified oligonucleotides offer many possibilities in utilizing their special features for a vast number of applications in nucleic acid based therapies and synthetic molecular biology. Locked nucleic acid analogues (alpha-/beta-LNA) are modifications having an extra ring of 2'-O,4'-C-methylene group in the furanose sugar. LNA strands have been shown to exhibit high binding affinity toward RNA and DNA strands, and the resultant duplexes show significantly high melting temperatures. In the present study, molecular dynamics (MD) simulations were performed on DNA-RNA hybrid duplexes by systematically modifying their deoxyribose sugars with locked nucleic acid analogues. Several geometrical and energetic analyses were performed using principal component (PCA) analysis and binding free energy methods to understand the consequence of incorporated isomeric LNA modifications on the structure, dynamics, and stability of DNA-RNA hybrid duplex. The beta-modification systematically changes the conformation of the DNA-RNA hybrid duplex whereas drastic changes are observed for alpha-modification. The fully modified duplexes have distinct properties compared to partial and unmodified duplexes, and the partly modified duplexes have properties intermediate to full strand and unmodified duplexes. The distribution of BI versus BII populations suggests that backbone rearrangement is minimal for beta-LNA modification in order to accommodate it in duplexes whereas extensive backbone rearrangement is necessary in order to incorporate alpha-LNA modification which subsequently alters the energetic and structural properties of the duplexes. The simulation results also suggest that the alteration of DNA-RNA hybrid properties depends on the position of modification and the gap between the modifications.