Calculated p<i>K</i><sub>a</sub> Values for a Series of Aza- and Deaza-Modified Nucleobases

Mlotkowski, Alan J.; Schlegel, H. Bernhard; Chow, Christine S.

doi:10.1021/acs.jpca.3c01358

Cited by 3 publications

(2 citation statements)

References 61 publications

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“…This study was later expanded to also include 20 aza and de-aza modifications. 40 calculations is broadly reported and accepted, this method also comes with some limitations.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In a previous study, Jones et al used quantum mechanics (QM) calculations as an ab initio technique to calculate 52 p K a values of 33 modified nucleobases with high accuracy (Figure ). This study was later expanded to also include 20 aza and de-aza modifications . While high accuracy for QM calculations is broadly reported and accepted, this method also comes with some limitations.…”

Section: Introductionmentioning

confidence: 99%

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Assessment of Nucleobase Protomeric and Tautomeric States in Nucleic Acid Structures for Interaction Analysis and Structure-Based Ligand Design

Kersten,

Archambault,

Köhler

2024

J. Chem. Inf. Model.

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With increasing interest in RNA as a therapeutic and a potential target, the role of RNA structures has become more important. Even slight changes in nucleobases, such as modifications or protomeric and tautomeric states, can have a large impact on RNA structure and function, while local environments in turn affect protonation and tautomerization. In this work, the application of empirical tools for pK a and tautomer prediction for RNA modifications was elucidated and compared with ab initio quantum mechanics (QM) methods and expanded toward macromolecular RNA structures, where QM is no longer feasible. In this regard, the Protonate3D functionality within the molecular operating environment (MOE) was expanded for nucleobase protomer and tautomer predictions and applied to reported examples of altered protonation states depending on the local environment. Overall, observations of nonstandard protomers and tautomers were well reproduced, including structural C+G:C(A) and A+GG motifs, several mismatches, and protonation of adenosine or cytidine as the general acid in nucleolytic ribozymes. Special cases, such as cobalt hexamine-soaked complexes or the deprotonation of guanosine as the general base in nucleolytic ribozymes, proved to be challenging. The collected set of examples shall serve as a starting point for the development of further RNA protonation prediction tools, while the presented Protonate3D implementation already delivers reasonable protonation predictions for RNA and DNA macromolecules. For cases where higher accuracy is needed, like following catalytic pathways of ribozymes, incorporation of QM-based methods can build upon the Protonate3D-generated starting structures. Likewise, this protonation prediction can be used for structure-based RNA-ligand design approaches.

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“…This study was later expanded to also include 20 aza and de-aza modifications. 40 calculations is broadly reported and accepted, this method also comes with some limitations.…”

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Assessment of Nucleobase Protomeric and Tautomeric States in Nucleic Acid Structures for Interaction Analysis and Structure-Based Ligand Design

Kersten,

Archambault,

Köhler

2024

J. Chem. Inf. Model.

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A novel Queuovirinae lineage of Pseudomonas aeruginosa phages encode dPreQ0 DNA modifications with a single GA motif that provide restriction and CRISPR Cas9 protection in vitro

Olsen,

Nielsen,

Cui

et al. 2023

Nucleic Acids Research

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Deazaguanine DNA modifications are widespread in phages, particularly in those with pathogenic hosts. Pseudomonas phage iggy substitutes ∼16.5% of its genomic 2′-deoxyguanosine (G) with dPreQ0, and the iggy deazaguanine transglycosylase (DpdA) is unique in having a strict GA target motif, not observed previously. The iggy PreQ0 modification is shown to provide protection against both restriction endonucleases and Cas9 (when present in PAM), thus expanding our understanding of the deazaguanine modification system, its potential, and diversity. Phage iggy represents a new genus of Pseudomonas phages within the Queuovirinae subfamily; which have very little in common with other published phage genomes in terms of nucleotide similarity (<10%) and common proteins (<2%). Interestingly, shared similarity is concentrated in dpdA and preQ0 biosynthesis genes. TEM imaging confirmed a siphovirus morphology with a prolate icosahedral head and a non-contractile flexible tail with one long central tail spike. The observed protective effect of the deazaguanine modification on the iggy DNA may contribute to its broad within-species host range. Phage iggy was isolated on Pseudomonas aeruginosa PAO1, but also infects PDO300, PAK, PA14, as well as 10 of 27 tested environmental isolates and 13 of 20 tested clinical isolates of P. aeruginosa from patients with cystic fibrosis.

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Four additional natural 7-deazaguanine derivatives in phages and how to make them

Liang

Balamkundu

Liu

et al. 2023

Nucleic Acids Research

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Bacteriophages and bacteria are engaged in a constant arms race, continually evolving new molecular tools to survive one another. To protect their genomic DNA from restriction enzymes, the most common bacterial defence systems, double-stranded DNA phages have evolved complex modifications that affect all four bases. This study focuses on modifications at position 7 of guanines. Eight derivatives of 7-deazaguanines were identified, including four previously unknown ones: 2′-deoxy-7-(methylamino)methyl-7-deazaguanine (mdPreQ1), 2′-deoxy-7-(formylamino)methyl-7-deazaguanine (fdPreQ1), 2′-deoxy-7-deazaguanine (dDG) and 2′-deoxy-7-carboxy-7-deazaguanine (dCDG). These modifications are inserted in DNA by a guanine transglycosylase named DpdA. Three subfamilies of DpdA had been previously characterized: bDpdA, DpdA1, and DpdA2. Two additional subfamilies were identified in this work: DpdA3, which allows for complete replacement of the guanines, and DpdA4, which is specific to archaeal viruses. Transglycosylases have now been identified in all phages and viruses carrying 7-deazaguanine modifications, indicating that the insertion of these modifications is a post-replication event. Three enzymes were predicted to be involved in the biosynthesis of these newly identified DNA modifications: 7-carboxy-7-deazaguanine decarboxylase (DpdL), dPreQ1 formyltransferase (DpdN) and dPreQ1 methyltransferase (DpdM), which was experimentally validated and harbors a unique fold not previously observed for nucleic acid methylases.

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

Cited by 3 publications

References 61 publications

Assessment of Nucleobase Protomeric and Tautomeric States in Nucleic Acid Structures for Interaction Analysis and Structure-Based Ligand Design

Assessment of Nucleobase Protomeric and Tautomeric States in Nucleic Acid Structures for Interaction Analysis and Structure-Based Ligand Design

A novel Queuovirinae lineage of Pseudomonas aeruginosa phages encode dPreQ0 DNA modifications with a single GA motif that provide restriction and CRISPR Cas9 protection in vitro

Four additional natural 7-deazaguanine derivatives in phages and how to make them

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

Cited by 3 publications

References 61 publications

Assessment of Nucleobase Protomeric and Tautomeric States in Nucleic Acid Structures for Interaction Analysis and Structure-Based Ligand Design

Assessment of Nucleobase Protomeric and Tautomeric States in Nucleic Acid Structures for Interaction Analysis and Structure-Based Ligand Design

A novel Queuovirinae lineage of Pseudomonas aeruginosa phages encode dPreQ0 DNA modifications with a single GA motif that provide restriction and CRISPR Cas9 protection in vitro

Four additional natural 7-deazaguanine derivatives in phages and how to make them

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Product

Resources

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