Structural and Energetic Impact of Non-Natural 7-Deaza-8-Azaadenine and Its 7-Substituted Derivatives on H-Bonding Potential with Uracil in RNA Molecules

Abstract

Abstract:Non-natural (synthetic) nucleobases, including 7-ethynyl-and 7-triazolyl-8-aza-7-deazaadenine, have been introduced in RNA molecules for targeted applications, and have been characterized experimentally. However, no theoretical characterization of the impact of these modifications on the structure and energetics of the corresponding H-bonded base pair is available. To fill this gap, we performed quantum mechanics calculations, starting with the analysis of the impact of the 8-aza-7-deaza modification of the adenine skeleton, and we moved then to analyze the impact of the specific substituents on the modified 8-aza-7-deazaadenine. Our analysis indicates that, despite of these severe structural modifications, the H-bonding properties of the modified base pair gratifyingly replicate those of the unmodified base pair. Similar behavior is predicted when the same skeleton modifications are applied to guanine when paired to cytosine. To stress further the H-bonding pairing in the modified adenine-uracil base pair, we explored the impact of strong electron donor and electron withdrawing substituents on the C7 position. Also in this case we found minimal impact on the base pair geometry and energy, confirming the validity of this modification strategy to functionalize RNAs without perturbing its stability and biological functionality.

Theoretical Characterization of the H-Bonding and Stacking Potential of Two Nonstandard Nucleobases Expanding the Genetic Alphabet

“…35,39,41,44,48−50 In the present study, we also derived the interaction energies in water, which were calculated using the same recipe as suggested by Sponer and co-workers. 48,74 To have an immediate and intuitive understanding of the impact of a specific modification, we introduced the modification energy, E mod , 36,38 defined as the energy difference between the interaction energy of the modified and that of the corresponding unmodified base pair (in this specific case, the Z:P base pair) Table 1. Geometry and Interaction Energy a of cWW Z:P and tWW Z:iP/iZ:P Base Pairs with 5-Substituted Z. Geometry and interaction energy of cWW G:C and tWW iG:C/G:iC are also reported for comparison.…”

Structural and Energetic Impact of Non‐natural 7‐Deaza‐8‐azaguanine, 7‐Deaza‐8‐azaisoguanine, and Their 7‐Substituted Derivatives on Hydrogen‐Bond Pairing with Cytosine and Isocytosine

“…We notice that both DAA and DAiG feature a N6 amino group, which can directly interact with the C7-substituents, as indicated by the modification in the electron density around it (Figure 6). [14]…”

“…[12] Our subsequent quantum mechanics analysis confirmed that the modified 7-deaza-8-azaadenine (DAA) and its 7-substituted derivatives have a negligible impact on the geometry and interaction energy of the base pairs they make with uracil, both in antiparallel and parallel doublehelix strands, and provided a theoretical explanation for that. [14] Similarly, several 7-deaza-8-aza analogues of guanine have also been synthesized and used in different applications in the last couple of decades, especially in the context of DNA. [15] A variety of 7-substituted 7-deaza-8-azaguanine (abbreviated here as DAG) residues, including 7-halogen derivatives, have been shown to stabilize the classical antiparallel DNA duplex, [16] while 7-deaza-8azaisoguanine (abbreviated here as DAiG) and its 7-halogen derivatives have been shown to stabilize the parallel DNA duplex when paired to self-complementary strands.…”

“…This is an approach we and others have been applying previously to evaluate the impact of natural and non-natural modifications on various H-bonded base pair systems. [14,21] First, we analyzed the impact of the N7 and C8 atoms translocation in the G skeleton, leading to the DAG modification. Next, we analyzed the impact of the ethynyl and triazole substituents on the C7 atom of DAG, as they are widely used for the chemical labeling of nucleic acids (especially using click chemistry reactivity), allowing to image and retrieve them even in whole organisms, thus monitoring their dynamics in living systems.…”

Enzymatic Formation of an Artificial Base Pair Using a Modified Adenine Nucleoside Triphosphate

“…This is a rather standard approach used in this kind of calculations. [69][70][71][72][73][74] download file view on ChemRxiv Manuscript.docx (2.22 MiB)…”