Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Apr 20;127(15):3526-3534.
doi: 10.1021/acs.jpca.3c01358. Epub 2023 Apr 10.

Calculated p Ka Values for a Series of Aza- and Deaza-Modified Nucleobases

Alan J Mlotkowski  1 , H Bernhard Schlegel  1 , Christine S Chow  1
Affiliations

Calculated p Ka Values for a Series of Aza- and Deaza-Modified Nucleobases

Alan J Mlotkowski et al. J Phys Chem A. .

Abstract

A variety of synthetic modified nucleobases have been used to investigate the structure and function of RNA and DNA or act as enzyme inhibitors. A set of these modifications involves the addition or removal of a nitrogen atom in the ring. These aza and deaza modifications have garnered interest as useful biochemical tools, but information on some of their physical characteristics is lacking. In this study, the B3LYP density functional with the 6-31+G(d,p) basis set and an implicit-explicit solvent model was used to perform ab initio quantum mechanical studies to estimate pKa values of aza- and deaza-modified nucleobases. A comparison between theoretical and known experimental pKa values was carried out, and adjustment factors were applied to 57 pKa values in the purine and pyrimidine data sets.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of the four canonical nucleosides/nucleobases. The structures and numbering schemes of pyrimidines (uridine and cytidine) and purines (adenosine and guanosine) are shown. Positions with reported aza modifications are numbered in blue, while deaza-modified positions are numbered in red.
Figure 2
Figure 2
Plot and linear regression fit for the theoretical and experimental pKa values of the purine aza/deaza modifications. The symbols indicate unmodified nucleobases (orange squares), natural modifications (red diamonds), and aza/deaza modifications (blue circles). The MAE for this set of data is 0.6.
Figure 3
Figure 3
Structures of aza-modified nucleobases. The modified positions are highlighted in blue. The deaza/aza nomenclature is given for the purine analogues formycin A and B (a8c9A and a8c9I, respectively).
Figure 4
Figure 4
Structures of G and a5c7G with different protonation status at N1.
Figure 5
Figure 5
Plot and linear regression fit for the theoretical and experimental pKa values of the aza modifications of the pyrimidine data set. The symbols indicate unmodified nucleobases (orange squares), natural modifications (red diamonds), and aza modifications (blue circles). The MAE for this set of data is 0.6.
Figure 6
Figure 6
Structures of aza-modified pyrimidines. Saturation of the N5–C6 double bond of a5U and a5C results in a change in N5 protonation.
See this image and copyright information in PMC

References

    1. Kapinos L. E.; Operschall B. P.; Larsen E.; Sigel H. Understanding the Acid–Base Properties of Adenosine: the Intrinsic Basicities of N1, N3 and N7. Chem. – Eur. J. 2011, 17, 8156–8164. 10.1002/chem.201003544. - DOI - PubMed
    1. Acharya P.; Cheruku P.; Chatterjee S.; Acharya S.; Chattopadhyaya J. Measurement of Nucleobase pKa Values in Model Mononucleotides Shows RNA-RNA Duplexes to be More Stable than DNA-DNA Duplexes. J. Am. Chem. Soc. 2004, 126, 2862–2869. 10.1021/ja0386546. - DOI - PubMed
    1. Tang C. L.; Alexov E.; Pyle A. M.; Honig B. Calculation of pKas in RNA: on the Structural Origins and Functional Roles of Protonated Nucleotides. J. Mol. Biol. 2007, 366, 1475–1496. 10.1016/j.jmb.2006.12.001. - DOI - PubMed
    1. Xia T.; SantaLucia J. Jr.; Burkard M. E.; Kierzek R.; Schroeder S. J.; Jiao X.; Cox C.; Turner D. H. Thermodynamic Parameters for an Expanded Nearest-Neighbor Model for Formation of RNA Duplexes with Watson–Crick Base Pairs. Biochemistry 1998, 37, 14719–14735. 10.1021/bi9809425. - DOI - PubMed
    1. Richardson K. E.; Znosko B. M. Nearest-Neighbor Parameters for 7-Deaza-Adenosine·Uridine Base Pairs in RNA Duplexes. RNA 2016, 22, 934–942. 10.1261/rna.055277.115. - DOI - PMC - PubMed