Substituted adenine quartets: interplay between substituent effect, hydrogen bonding, and aromaticity

Abstract

Adenine, one of the components of DNA/RNA helices, has the ability to form self-organizing structures with cyclic hydrogen bonds (A₄), similar to guanine quartets. Here, we report a computational investigation of the effect of substituents (X = NO₂, Cl, F, H, Me, and NH₂) on the electronic structure of 9H-adenine and its quartets (A₄-N1, A₄-N3, and A₄-N7). DFT calculations were used to show the relationships between the electronic nature of the substituents, strength of H-bonds in the quartets, and aromaticity of five- and six-membered rings of adenine. We demonstrated how the remote substituent X modifies the proton-donating properties of the NH₂ group involved in the H-bonds within quartets and how the position of the substituent and its electronic nature affect the stability of the quartets. We also showed the possible changes in electronic properties of the substituent and aromaticity of adenine rings caused by tetramer formation. The results indicate that the observed relationships depend on the A₄ type. Moreover, the same substituent can both strengthen and weaken intermolecular interactions, depending on the substitution position.

Fig. 1. Analyzed tetramers of adenine with places of substitution marked, C8, N9, and C2, respectively.

Fig. 2. Dependences of cSAR(NH₂) on cSAR(X) for C2-/C8- (a) and N9- (b) substituted adenine monomers and tetramers. More positive cSAR(X) values correspond to more electron-donating substituents.

Fig. 3. Relationships between the bonding energies, E_HB, and cSAR(X) of substituent for the studied adenine quartets.

Fig. 4. Relationships between bonding energy and N⋯H length, d_N⋯H, for the studied substituted tetramers.

Fig. 5. Structures of A₄-N3, A₄-N3(N9-NO₂) and A₄-N7(N9-NO₂) systems with bond critical points: a is a typical H-bond in quartet, b – additional CH⋯N contact, c – additional O⋯HN contact.