There are numerous modified nucleobases, which are believed to play roles in fine-tuning structure and function of various RNA molecules. Modifications of nucleobases have a wide range of effects including participating in regulation of expression and response to stress in the cell. Despite a growing wealth of knowledge, specific details about modifications are still not known. The pKa value is a defining characteristic of nucleobases, which is used to understand base-pairing energetics of modified nucleobases. Nucleobases and their modifications contain one or more protonation/deprotonation sites that have unique pKa values. Modifications on nucleobases affect the pKa values, resulting in a change of nucleobase behavior. To gain an understanding of the impacts of modification of nucleobases, the pKa must be determined. In this study, we calculated the pKa values of modified nucleobases by performing ab initio quantum mechanical calculations using the Gaussian 09 program using the B3LYP/6-31+G(d,p) method with a combination of implicit-explicit solvation. This method involved the use of explicit water molecules forming hydrogen bonds with the nucleobases surrounded by an implicit solvation field. The pKa values were calculated from the change in the free energy between protonated and deprotonated forms of the nucleobases and the energy of the solvated proton. Understanding the pKa values of modified nucleobases will give insight into the specific structure and energetic impacts of modifications on the nucleobases of RNA and DNA.

Theoretical pKa calculations of modified nucleobases using a hybrid solvation model

ACS Spring Meeting 2021

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