yDNA versus yyDNA pyrimidines: computational analysis of the effects of unidirectional ring expansion on the preferred sugar-base orientation, hydrogen-bonding interactions and stacking abilities.

The properties of natural, y- and yy-pyrimidines are compared using computational (B3LYP, MP2) methods. Ring expansion upon incorporation of benzene or naphthalene into the natural pyrimidines affects the preferred orientation of the base about the glycosidic bond in the corresponding nucleoside to a similar extent. Specifically, although the natural pyrimidines preferentially adopt the anti orientation with respect to the 2'-deoxyribose moiety, the expanded analogues will likely display (anti/syn) conformational heterogeneity, which may lead to alternate hydrogen-bonding modes in double-stranded duplexes. Nevertheless, the A:T Watson-Crick hydrogen-bond strengths do not significantly change upon base expansion, while the G:C interaction energy is slightly strengthened upon incorporation of either expanded pyrimidine. The largest effect of base expansion occurs in the stacking energies. Specifically, the maximum (most negative) stacking energies in isolated dimers formed by aligning the nucleobase centers of mass can be increased up to 45% by inclusion of a single y-pyrimidine and up to 55% by consideration of a yy-pyrimidine. Similar increases in the stacking interactions are found when a simplified duplex model composed of two stacked (hydrogen-bonded) base pairs is considered, where both the intrastrand and interstrand stacking interactions can be increased and the effects are more pronounced for the yy-pyrimidines. Moreover, the total stability (sum of all hydrogen-bonding and stacking interactions) is greater for duplexes containing expanded yy-pyrimidines compared to y-pyrimidines, which is mainly due to enhanced stacking interactions. Thus, our calculations suggest that multiple unidirectional increases in the size of the nucleobase spacer can continuously enhance the stability of expanded duplexes.