Calculations of pKa Values for a Series of Fluorescent Nucleobase Analogues

Nucleobases play diverse structural and functional roles in biological systems. Understanding the fundamental properties of nucleobases is important for their applications as chemical probes of nucleic acid function. As the nucleobases are modified to tune their fluorescence or binding properties, their physical properties such as pKa may also change. Unlike the canonical nucleobases, modified nucleobases are less well understood in terms of their acid-base properties. Previously, theoretical pKa values of canonical, naturally modified, and aza-/deaza-modified nucleobases were determined. In this study, the theoretical pKa values for 25 different fluorescent modified nucleobases (55 total pKa values) were calculated by using an ab initio quantum mechanical method employing the B3LYP density functional with 6-31+G(d,p) basis set along with an implicit–explicit solvation model. The results of these computations are compared to known experimental pKa values. The ability to estimate theoretical pKa values will be beneficial for further development and applications of fluorescent nucleobases.