Density functional theory studies on cytosine analogues for inducing double-proton transfer with guanine

Abstract

To induce double-proton transfer (DPT) with guanine in a biological environment, 12 cytosine analogues (Ca) were formed by atomic substitution. The DPT reactions in the Watson–Crick cytosine–guanine model complex (Ca0G) and 12 modified cytosine–guanine complexes (Ca1-12G) were investigated using density functional theory methods at the M06-2X/def2svp level. The intramolecular proton transfers within the analogues are not facile due to high energy barriers. The hydrogen bond lengths of the Ca1-12G complexes are shorter than those in the Ca0G complex, which are conducive to DPT reactions. The DPT energy barriers of Ca1-12G complexes are also lower than that of the Ca0G complex, in particular, the barriers in the Ca7G and Ca11G complexes were reduced to −1.33 and −2.02 kcal/mol, respectively, indicating they are significantly more prone to DPT reactions. The DPT equilibrium constants of Ca1-12G complexes range from 1.60 × 100 to 1.28 × 107, among which the equilibrium constants of Ca7G and Ca11G are over 1.0 × 105, so their DPT reactions may be adequate. The results demonstrate that those cytosine analogues, especially Ca7 and Ca11, are capable of inducing DPT with guanine, and then the guanine tautomer will form mismatches with thymine during DNA replication, which may provide new strategies for gene therapy.

The influence of external electric fields on proton transfer tautomerism in the guanine–cytosine base pair

“…Researchers have used DFT and QM/MM to investigate how different external factors, e.g., intercalation with cis-platin, 8 analogous nucleobases, 9 and intense external electric fields [10][11][12] affect the stability of the proton transfer tautomers. In addition, a wide range of studies have investigated how the population of different excited states influence the mechanism of proton transfer in the absence [13][14][15] and presence of external electric fields.…”

Electromagnetic bioeffects: a multiscale molecular simulation perspective

“…122 For instance, pairing of unnatural nucleobases, ionizing radiation and intercalating agents have been found to influence the stability of these tautomers. 123–125 Guanine–cytosine (G:C) base-pairs are known to be more susceptible to tautomeric induced mutations, with adenine–thymine (A:T) pairs showing greater resistance. 126–128 As different tautomers can possess markedly different electrostatic properties ( i.e.…”

Importance of Sugar–Phosphate Backbone and Counterions to First-Principles Modeling of Nucleobases

“…Brancolini et al 18 used a backbone-free model to study the electronic properties of metal-modified DNA. Just recently, Xue et al 19 performed a first-principles study on cytosine without backbone to understand the double-proton transfer process with guanine.…”