Molecular mechanics and dynamics studies on two structurally related amide-modified DNA backbones for antisense technology Original Research Article

The effect of the replacement of the natural phosphodiester linkage -C3′OPO2− -OCH2C4′- in the DNA strand of RNA-DNA hybrid duplexes by either of the two amide linkages -C3′-CH2-CO-NH-CH2-C4′- or -C3′CH2NHCOCH2C4′ has been investigated by molecular mechanics (MM) and molecular dynamics (MD) simulations. Conformational analysis has been used to assess various low-energy conformers of the amide-modified backbones. MD simulations have been carried out to study the dynamic behavior of the modified duplexes. The modified RNA-DNA hybrid double helices kept a conservative base pairing scheme during the MD simulations. Although the general behavior has been found to be similar to that of the corresponding wild-type hybrid duplexes, some notable differences, especially regarding the sugar puckering in the amide-modified DNA strands, have been observed. The behavior of the RNA strands in the hybrid duplexes has not been affected by the modified DNA strands and is similar to that in wild-type RNA-DNA duplexes.