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

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 (Ca(0)G) and 12 modified cytosine–guanine complexes (Ca(1-12)G) 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 Ca(1-12)G complexes are shorter than those in the Ca(0)G complex, which are conducive to DPT reactions. The DPT energy barriers of Ca(1-12)G complexes are also lower than that of the Ca(0)G complex, in particular, the barriers in the Ca(7)G and Ca(11)G 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 Ca(1-12)G complexes range from 1.60 × 10(0) to 1.28 × 10(7), among which the equilibrium constants of Ca(7)G and Ca(11)G are over 1.0 × 10(5), so their DPT reactions may be adequate. The results demonstrate that those cytosine analogues, especially Ca(7) and Ca(11), 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.