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

Abstract

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.

Can Cyanuric Acid and 2,4,6‐Triaminopyrimidine Containing Ribonucleosides be Components of Prebiotic RNA? Insights from QM Calculations and MD Simulations

“…As a step towards testing this hypothesis, we analyze the inherent stacking potential of CA and TAP. Previous computational studies have characterized the stacking interactions in dimers composed of nucleobases and/or other heterocycles . Despite the dependence of these interactions on translational (i. e. vertical and horizontal monomer displacements) and rotational (i. e., mutual rotation of the interacting monomers) geometric variables, these studies reveal the stacking strength most prominently depends on the rotational parameter .…”

“…Stacking interactions within the CA-TAP, CA-CA and TAP-TAP dimers, as well as dimers between CA or TAP and a natural base, were characterized using B3LYP-D3/6-31G(d,p) optimized monomers arranged at a vertical separation of 3.3 Å. [40][41][42][43] The single-ringcontaining monomers (CA, TAP, C and U) were stacked with respect to the ring centers, while the purines (A and G) were stacked with respect to the center of the 9-member ring formed by all heavy atoms constituting the two-fused rings. The stacking energy profiles were analyzed at the B3LYP-D3/6-311 + G(2df,p) level for rotation about α, which was set equal to 0°w…”

“…[53][54][55] Thus, in the present work, we consider the dependence of the strength of the stacking interactions on the angle of rotation (α) between monomers aligned with respect to their ring centers at a fixed vertical distance (3.3 Å), which is the average separation between bases in nucleic acid helices, [57,58] and was chosen to parallel studies on nucleobase dimers. [40][41][42][43]…”

“…B3LYP‐D3/6‐31G(d,p) zero‐point vibrational energy (ZPVE) corrections were then added to B3LYP‐D3/6‐311+G(2df,p) single‐point energies to calculate the hydrogen‐bond strengths of the pairs involving TAP, CA and/or canonical nucleobases. Stacking interactions within the CA‐TAP, CA‐CA and TAP‐TAP dimers, as well as dimers between CA or TAP and a natural base, were characterized using B3LYP‐D3/6‐31G(d,p) optimized monomers arranged at a vertical separation of 3.3 Å . The single‐ring‐containing monomers (CA, TAP, C and U) were stacked with respect to the ring centers, while the purines (A and G) were stacked with respect to the center of the 9‐member ring formed by all heavy atoms constituting the two‐fused rings.…”

Künstliche genetische Systeme bestehend aus vergrößerten Basenpaaren

“…Es wurde auch ein starkes Potential für Fehlpaarungen gefunden, hauptsächlich aufgrund von y-yT und T-yC-Fehlpaarung. [32] Eine weitere ausführliche theoretische Studie untersuchte den wichtigen Punkt der Tautomerie. [30] Nach diesen Erfolgen bei der Benzo-Homologisierung untersuchten wir, ob eine weitere "Streckung" der Basen mçglich ist.…”