Cytosine Derivatives Form Hemiprotonated Dimers in Solution and the Gas Phase

Moehlig, Aaron R.; Djernes, Katherine E.; Krishnan, V. Mahesh; Hooley, Richard J.

doi:10.1021/ol300861r

Cited by 10 publications

(18 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8,9 Association of N-substituted cytosines with their conjugate acids has recently been demonstrated in solution, as well. 10 On the one hand, the majority of crystal structures show that the distances r NO and r ON shown in Fig. 1 differ by between 0.15 and 0.2 Å in the equilibrium geometry, consistent with the solid phase NMR spectra reported below.…”

Section: Introductionsupporting

confidence: 82%

Proton-bound dimers of 1-methylcytosine and its derivatives: vibrational and NMR spectroscopy

Ung

Moehlig

Kudla

et al. 2013

Phys. Chem. Chem. Phys.

Self Cite

View full text Add to dashboard Cite

Proton-bound dimers of 1-methylcytosine and its derivatives: vibrational and NMR spectroscopy Ung, H.U.; Moehlig, A.R.; Kudla, R.A.; Mueller, L. J.; Oomens, J.; Berden, G.; Morton, T.H. Published in:Physical Chemistry Chemical Physics DOI:10.1039/c3cp52260aLink to publication Citation for published version (APA):Ung, H. U., Moehlig, A. R., Kudla, R. A., Mueller, L. J., Oomens, J., Berden, G., & Morton, T. H. (2013). Protonbound dimers of 1-methylcytosine and its derivatives: vibrational and NMR spectroscopy. Physical Chemistry Chemical Physics, 15(43), 19001-19012. DOI: 10.1039/c3cp52260a General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Vibrational spectroscopy and NMR demonstrate that the proton-bound dimer of 1-methylcytosine, 1, has an unsymmetrical structure at room temperature. In the gas phase, investigation of isolated homodimer 1 reveals five fundamental NH vibrations by IR Multiple Photon Dissociation (IRMPD) action spectroscopy. The NHÁ Á ÁN stretching vibration between the two ring nitrogens exhibits a frequency of 1570 cm À1 , as confirmed by examination of the proton-bound homodimers of 5-fluoro-1-methycytosine, 2, and of 1,5-dimethylcytosine, 3, which display absorptions in the same region that disappear upon deuterium substitution. 13 C, and 15 N NMR of the solid iodide salt of 1 confirm the nonequivalence of the two rings in the anhydrous proton-bound homodimer at room temperature. IRMPD spectra of the three possible heterodimers also show NHÁ Á ÁN stretches in the same domain, and at least one of the heterodimers, the proton-bound dimer of 1,5-dimethylcytosine with 1-methylcytosine, exhibits two bands suggestive of the presence of two tautomers close in energy. IntroductionDimerization of nucleobases by H + bridging represents a nonWatson-Crick form of association whose biological relevance has emerged in recent years. Many questions remain regarding the structure and dynamics of the proton bridge. This paper presents an examination of proton-bound dimers of 1-methylcytosine and its derivatives using several approaches -solid state NMR (ssNMR), vibrational spectroscopy, X-ray diffraction, and computation -in order to answer two questions. First, is the bridging proton shared equally by both bases in the equilibrium geometry? Second, does a nor...

show abstract

Section: Introductionsupporting

confidence: 82%

Proton-bound dimers of 1-methylcytosine and its derivatives: vibrational and NMR spectroscopy

Ung

Moehlig

Kudla

et al. 2013

Phys. Chem. Chem. Phys.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The nitrogenous buffers were speculated to provide a buffered environment to generate the active intermediate to enhance the DNAzyme activity . It is known that the N3‐position of cytosine can be protonated under slightly acid condition . Protonated cytosine can also be found in DNA sequences, such as C‐rich DNA .…”

Section: Resultsmentioning

confidence: 99%

“…[23] It is known that the N3-positiono fc ytosine can be protonated under slightly acid condition. [25] Protonated cytosine can also be found in DNA sequences, such as C-rich DNA. [26] Therefore, it is possible that the flankingd (CCC) sequences can accept some protons and provide ab etter buffer capacitya gainst furtherp rotonation, leading to al ower sensitivity to pH changes.…”

Section: The Effect Of the Ph Value On The Catalyticactivity Of Dnazymementioning

confidence: 99%

Activity Enhancement of G‐Quadruplex/Hemin DNAzyme by Flanking d(CCC)

Chang

Gong

Ding

et al. 2016

Chemistry A European J

View full text Add to dashboard Cite

G-quadruplex (G4)/hemin DNAzymes have been extensively applied in bioanalysis and molecular devices. However, their catalytic activity is still much lower than that of proteinous enzymes. The G4/hemin DNAzyme activity is correlated with the G4 conformations and the solution conditions. However, little is known about the effect of the flanking sequences on the activity, though they are important parts of G4s. Here, we report sequences containing d(CCC), flanked on both ends of the G4-core sequences remarkably enhance their DNAzyme activity. By using circular dichroism and UV-visible spectroscopy, the d(CCC) flanking sequences were demonstrated to improve the hemin binding affinity to G4s instead of increasing the parallel G4 formation, which might explain the enhanced DNAzyme activity. Meanwhile, the increased hemin binding ability promoted the degradation of hemin within the DNAzyme by H2O2. Furthermore, the DNAzyme with d(CCC) flanking sequences showed strong tolerance to pH value changes, which makes it more suitable for applications requiring wide pH conditions. The results highlight the influence of the flanking sequences on the DNAzyme activity and provide insightful information for the design of highly active DNAzymes.

show abstract

“…Both G4s and iMs are four-stranded tetraplexes that can be formed by multiple individual single strands or by internal folding of a single-strand (ss) DNA. 1,2 iMs are formed from cytosine repeats in C-rich DNA at slightly acidic pH, where unprotonated and protonated C–C + base pairs intercalate and stabilize the structure. 3,4 In genomic DNA, G- and C-rich regions capable of forming G4/iMs are enriched in regulatory elements of genes, particularly around the transcriptional start sites (TSS).…”

mentioning

confidence: 99%

Epigenetic Modification, Dehydration, and Molecular Crowding Effects on the Thermodynamics of i-Motif Structure Formation from C-Rich DNA

et al. 2014

View full text Add to dashboard Cite

DNA sequences with the potential to form secondary structures such as i-motifs (iMs) and G-quadruplexes (G4s) are abundant in the promoters of several oncogenes and, in some instances, are known to regulate gene expression. Recently, iM-forming DNA strands have also been employed as functional units in nanodevices, ranging from drug delivery systems to nanocircuitry. To understand both the mechanism of gene regulation by iMs and how to use them more efficiently in nanotechnological applications, it is essential to have a thorough knowledge of factors that govern their conformational states and stabilities. Most of the prior work to characterize the conformational dynamics of iMs have been done with iM-forming synthetic constructs like tandem (CCT)n repeats and in standard dilute buffer systems. Here, we present a systematic study on the consequences of epigenetic modifications, molecular crowding, and degree of hydration on the stabilities of an iM-forming sequence from the promoter of the c-myc gene. Our results indicate that 5-hydroxymethylation of cytosines destabilized the iMs against thermal and pH-dependent melting; contrarily, 5-methylcytosine modification stabilized the iMs. Under molecular crowding conditions (PEG-300, 40% w/v), the thermal stability of iMs increased by ∼10 °C, and the pKa was raised from 6.1 ± 0.1 to 7.0 ± 0.1. Lastly, the iM’s stability at varying degrees of hydration in 1,2-dimethoxyethane, 2-methoxyethanol, ethylene glycol, 1,3-propanediol, and glycerol cosolvents indicated that the iMs are stabilized by dehydration because of the release of water molecules when folded. Our results highlight the importance of considering the effects of epigenetic modifications, molecular crowding, and the degree of hydration on iM structural dynamics. For example, the incorporation of 5-methylycytosines and 5-hydroxymethlycytosines in iMs could be useful for fine-tuning the pH- or temperature-dependent folding/unfolding of an iM. Variations in the degree of hydration of iMs may also provide an additional control of the folded/unfolded state of iMs without having to change the pH of the surrounding matrix.

show abstract

Cytosine Derivatives Form Hemiprotonated Dimers in Solution and the Gas Phase

Abstract: Hemiprotonated dimers of cytosine derivatives, implicated in the formation of the i-motif of DNA, have been created in solution and the gas phase. The mechanism of dimerization has been analyzed by mass spectrometry and multidimensional NMR spectroscopy.

Cited by 10 publications

References 21 publications

Proton-bound dimers of 1-methylcytosine and its derivatives: vibrational and NMR spectroscopy

Proton-bound dimers of 1-methylcytosine and its derivatives: vibrational and NMR spectroscopy

Activity Enhancement of G‐Quadruplex/Hemin DNAzyme by Flanking d(CCC)

Epigenetic Modification, Dehydration, and Molecular Crowding Effects on the Thermodynamics of i-Motif Structure Formation from C-Rich DNA

Contact Info

Product

Resources

About