Hydrogen-Bond Acid/Base Catalysis: A Density Functional Theory Study of Protonated Guanine-(Substituted) Cytosine Base Pairs as Models for Nucleophilic Attack on Mitomycin in DNA

The mechanism of alkylation at the exocyclic nitrogen of guanine in G·C base pairs has been studied using density functional theory at the B3LYP/D95** level. Protonation of the amino group was used as a model for this reaction. The calculations indicate that the reaction is facilitated by a temporary transfer of the H-bonding hydrogen from the guanine amino position to the cytosine oxygen within the H-bond. Thus, the cytosine “loans” its basicity to the guanine within the H-bonded base pair. These calculations explain the previously observed dependence of guanine alkylation upon the substituent at the 5-position of cytosine. The generality of catalysis via the temporary transfer of a H-bonding hydrogen within an H-bond, hydrogen-bond, acid/base catalysis (HBA/BC), is discussed. This form of catalysis might be important in biochemistry, materials science, and the solid state.