We studied for the first time 16 tautomers/rotamers of diphosphocytosine by four computational methods. Some of these tautomers/rotamers are isoenergetic although they have different structures. High-level electron correlation MP2 and MP4(SDQ) ab initio methods and density functional methods employing a B3LYP and the new M06-2X functional were used to study the structure and relative stability of 16 tautomers/rotamers of diphosphocytosine. The dienol tautomers of diphosphocytosine are shown to be much more stable than the keto-enol and diketo forms. The tautomers/rotamers stability could be ranked as PC3？=？PC12？<？PC2？=？PC11？<？PC1？<？PC10？<？PC8？<？PC9？<？PC15？<？PC16？<？PC6？~？PC7？<？PC13？<？PC4？~？PC14？<？PC5. This stability order was discussed in the light of stereo and electronic factors. Solvation effect has been modeled in a high dielectric solvent, water using the polarized continuum model (PCM). Consideration of the solvent causes some reordering of the relative stability of diphosphocytosine tautomers: PC3？~？PC12？~？PC2？~？PC11？<？PC1？<？PC10？<？PC8？<？PC9？<？PC15？~？PC16？<？PC13？<？PC6？~？PC7？~？PC14？<？PC4？~？PC5. 1. Introduction DNA is a naturally occurring biological macromolecule, containing thousands of nucleic acid bases, and it is of prime importance in genetic determination [1]. The five nucleic acid bases, cytosine, thymine, uracil, adenine, and guanine, found in DNA and RNA control the replication of DNA, store information required to synthesize proteins, and translate this information to the protein. Tautomerism is a well-known phenomenon occurring in nucleic acid bases [2–16], in which proton transfer from the heterocyclic ring center to an exocyclic oxo- or imino- group leads to the formation of either an –OH or an –NH2 groups. These processes are known as keto-enol or imino-amino tautomerism, respectively. Tautomerism, a sort of isomerism, plays an important role in organic chemistry, medicinal chemistry, pharmacology, and molecular biology. Tautomerism partially explains the structure of nucleic acids and their mutations [17]. In DNA bases, tautomerization results in altered base pairing configurations or mispairing due to changes in hydrogen-bonding capabilities. DNA mutations are likely to be caused by such alterations. Cytosine is one of the building pyrimidine nucleobases of RNA. A large amount of experimental [18–34] and theoretical work [35–58] has been carried out in order to elucidate the structure of cytosine and its tautomers. Chemically modified bases have attracted extensive interest due to their numerous pharmacological, biochemical, and
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