The conformational study of two carbocyclic nucleosides: why carbocyclic nucleic acids (CarNAs) form more stable duplexes with RNA than DNA does

Abstract

Replacement of the furanose moiety of DNA with a cyclopentane ring produces a modified sugar analogue: Carbocyclic nucleic acid (CarNA). UV melting-temperature experiments demonstrate that the incorporation of 2'-deoxycarbaguanosine ((c)G) and 2'-deoxyaristeromycin ((c)A) of carbocyclic nucleosides into a DNA strand increases the stability of the CarNA/RNA hybrid. Circular Dichroism (CD) study indicates that the CarNA/RNA hybrid adopts an A-like conformation. To elucidate the molecular basis of the increased stability of the CarNA/RNA, the conformation of (c)G and (c)A were examined by (1)H NMR conformational analysis of (3)J(HH) coupling constants and ab initio molecular orbital (MO) calculations. These results show that the populations of N-type of (c)G and (c)A are higher than those of dG and dA, respectively, at different temperatures [For example, 37% (N%) of (c)G vs. 28%of dG, 36% (N%) of (c)A vs. 25% of dA at 278 K], which suggest that the cyclopentane rings of (c)G and (c)A prefer the N-type conformation in two-state N-S pseudorotional equilibrium in comparison with the furanose rings of dG and dA. The DeltaH degrees of (c)G (DeltaH degrees = - 0.43 kcal mol(-1)) and (c)A (DeltaH degrees = - 0.41kcal mol(-1)) are lower than that of dG (dG = - 1.8 kcal mol(-1)) and dA (dA = - 1.0 kcal mol(-1)), respectively, which suggest that the gauche effect in the (c)A and (c)G driving N-S pseudorotional equilibrium to S-type is reduced by replacement of the 4'-oxygen by a CH(2) group. These results suggest that the preferred N-type of the (c)G and (c)A leads to the A-like conformation, which contributes to the stability of CarNA/RNA hybrid.