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 (Ca_1-12G) 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 Ca_1-12G complexes are shorter than those in the Ca₀G complex, which are conducive to DPT reactions. The DPT energy barriers of Ca_1-12G 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 Ca_1-12G 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.