Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Studies on the Non-covalent Interactions (Stereoelectronics, Stacking and Hydrogen Bonding) in the Self-assembly of DNA and RNA
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is based on ten publications (Papers I-X). The phosphodiester backbone makes DNA or RNA to behave as polyelectrolyte, the pentose sugar gives the flexibility, and the aglycones promote the self-assembly or the ligand-binding process. The hydrogen bonding, stacking, stereoelectronics and hydration are few of the important non-covalent forces dictating the self-assembly of DNA/RNA. The pH-dependent thermodynamics clearly show (Papers I and II) that a change of the electronic character of aglycone modulates the conformation of the sugar moiety by the tunable interplay of stereoelectronic anomeric and gauche effects, which are further transmitted to steer the sugar-phosphate backbone conformation in a cooperative manner. 3'-anthraniloyl adenosine (a mimic of 3'-teminal CCAOH of the aminoacyl-tRNAPhe) binds to EF-Tu*GTP in preference over 2'-anthraniloyl adenosine, thereby showing (Paper III) that the 2’-endo sugar conformation is a more suitable mimic of the transition state geometry than the 3’-endo conformation in discriminating between correctly and incorrectly charged aminoacyl-tRNAPhe by EF-Tu during protein synthesis. The presence of 2'-OH in RNA distinguishes it from DNA both functionally as well as structurally. This work (Paper IV) provides straightforward NMR evidence to show that the 2'-OH is intramolecularly hydrogen bonded with the vicinal 3'-oxygen, and the exposure of the 3'-phosphate of the ribonucleotides to the bulk water determines the availability of the bound water around the vicinal 2'-OH, which then can play various functional role through inter- or intramolecular interactions. The pH-dependent 1H NMR study with nicotinamide derivatives demonstrates (Paper V) that the cascade of intramolecular cation (pyridinium)-π(phenyl)-CH(methyl) interaction in edge-to-face geometry is responsible for perturbing the pKa of the pyridine-nitrogen as well as for the modulation of the aromatic character of the neighboring phenyl moiety, which is also supported by the T1 relaxation studies and ab initio calculations. It has been found (Papers VI-IX) that the variable intramolecular electrostatic interaction between electronically coupled nearest neighbor nucleobases (steered by their respective microenvironments) can modulate their respective pseudoaromatic characters. The net result of this pseudoaromatic cross-modulation is the creation of a unique set of aglycones in an oligo or polynucleotide, whose physico-chemical properties are completely dependent upon the propensity and geometry of the nearest neighbor interactions (extended genetic code). The propagation of the interplay of these electrostatic interactions across the hexameric ssDNA chain is considerably less favoured (effectively up to the fourth nucleobase) compared to that of the isosequential ssRNA (up to the sixth nucleobase). The dissection of the relative strength of basepairing and stacking in a duplex shows that stability of DNA-DNA duplex weakens over the corresponding RNA-RNA duplexes with the increasing content of A-T/U base pairs, while the strength of stacking of A-T rich DNA-DNA duplex increases in comparison with A-U rich sequence in RNA-RNA duplexes (Paper X).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 54
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 914
Keywords [en]
Bioorganic chemistry, nucleic acids, NMR, Stereoelectronic effects, Hydrogen Bonding, Stacking
Keywords [sv]
Bioorganisk kemi
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-3825ISBN: 91-554-5821-1 (print)OAI: oai:DiVA.org:uu-3825DiVA, id: diva2:163775
Public defence
2003-12-19, B7:113a, Floor 1, Biomedical Centre, Husargatan 3, Uppsala, 13:00
Opponent
Supervisors
Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
List of papers
1. The Transmission of the Electronic Character of Guanin-9-yl Drives the Sugar-phosphate Backbone Torsions in Guanosine 3',5'-bisphosphate.
Open this publication in new window or tab >>The Transmission of the Electronic Character of Guanin-9-yl Drives the Sugar-phosphate Backbone Torsions in Guanosine 3',5'-bisphosphate.
Show others...
1999 In: Angew. Chem. Int. Ed., Vol. 38, no 24, p. 3645-3650Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91143 (URN)
Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
2. The RNA Molecular Wire: The pH-Dependent Change in Electronic Character of Adenine-9-yl is Transmitted to Drive the Sugar-Phosphate Backbone Torsions in Adenosine 3', 5'-bisphosphate
Open this publication in new window or tab >>The RNA Molecular Wire: The pH-Dependent Change in Electronic Character of Adenine-9-yl is Transmitted to Drive the Sugar-Phosphate Backbone Torsions in Adenosine 3', 5'-bisphosphate
Show others...
2000 In: J. Phys. Org. Chem., Vol. 13, p. 300-305Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91144 (URN)
Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
3. The Strength of the 3'-gauche effect Dictates the Structure of 3'-anthraniloyladenosine and its 5'-phosphate, Two Analogues of the 3'-end of Aminoacyl tRNA
Open this publication in new window or tab >>The Strength of the 3'-gauche effect Dictates the Structure of 3'-anthraniloyladenosine and its 5'-phosphate, Two Analogues of the 3'-end of Aminoacyl tRNA
Show others...
1999 In: J. Chem. Soc. Perkin 2, p. 1531-1536Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91145 (URN)
Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
4. The Hydrogen Bonding and Hydration of 2'-OH in Adenosine and Adenosine 3'-ethylphosphate
Open this publication in new window or tab >>The Hydrogen Bonding and Hydration of 2'-OH in Adenosine and Adenosine 3'-ethylphosphate
2002 In: J. Org. Chem., Vol. 67, no 6, p. 1852-1865Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91146 (URN)
Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
5. A Repertoire of Pyridinium-Phenyl-Methyl Cross-Talk through a Cascade of Intramolecular Electrostatic Interactions
Open this publication in new window or tab >>A Repertoire of Pyridinium-Phenyl-Methyl Cross-Talk through a Cascade of Intramolecular Electrostatic Interactions
Show others...
2003 In: J. Org. Chem., Vol. 68, no 4, p. 1529-1538Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91147 (URN)
Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
6. Cross-Modulation of Physicochemical Character of Aglycones in Dinucleoside (3'→5') monophosphates by the Nearest Neighbor Interaction in the Stacked State
Open this publication in new window or tab >>Cross-Modulation of Physicochemical Character of Aglycones in Dinucleoside (3'→5') monophosphates by the Nearest Neighbor Interaction in the Stacked State
2002 In: J. Am. Chem. Soc., Vol. 124, no 46, p. 13722-13730Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91148 (URN)
Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
7. Tandem Electrostatic Effect From the First to the Third Aglycon in the Trimeric RNA Owing to the Nearest-neighbor Stacking
Open this publication in new window or tab >>Tandem Electrostatic Effect From the First to the Third Aglycon in the Trimeric RNA Owing to the Nearest-neighbor Stacking
2003 In: J. Am. Chem. Soc., Vol. 125, no 8, p. 2094-2100Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91149 (URN)
Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
8. Cross-Modulation of the pKa of Nucleobases in a Single-Stranded Hexameric-RNA Due to Tandem Electrostatic Nearest-Neighbor Interactions
Open this publication in new window or tab >>Cross-Modulation of the pKa of Nucleobases in a Single-Stranded Hexameric-RNA Due to Tandem Electrostatic Nearest-Neighbor Interactions
Show others...
2003 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 125, no 33, p. 9948-9961Article in journal (Refereed) Published
Abstract [en]

The pH titration studies (pH 6.7-12.1) in a series of dimeric, trimeric, tetrameric, pentameric, and hexameric oligo-RNA molecules [GpA (2a), GpC (3a), GpApC (5), GpA(1)pA(2)pC (6), GpA(1)pA(2)pA(3)pC (7), GpA(1)pA(2)pA(3)pA(4)pC (8)] have shown that the pK(a) of N(1)-H of 9-guaninyl could be measured not only from its own deltaH8G, but also from the aromatic marker protons of other constituent nucleobases. The relative chemical shift differences [Deltadelta((N)(-)(D))] between the protons in various nucleotide residues in the oligo-RNAs at the neutral (N) and deprotonated (D) states of the guanine moiety show that the generation of the 5'-(9-guanylate ion) in oligo-RNAs 2-8 reduces the stability of the stacked helical RNA conformation owing to the destabilizing anion(G(-))-pi/dipole(Im(delta)(-)) interaction. This destabilizing effect in the deprotonated RNA is, however, opposed by the electrostatically attractive atom-pisigma (major) as well as the anion(G(-))-pi/dipole(Py(delta)(+)) (minor) interactions. Our studies have demonstrated that the electrostatically repulsive anion(G(-))-pi/dipole(Im(delta)(-)) interaction propagates from the first to the third nucleobase quite strongly in the oligo-RNAs 6-8, causing destacking of the helix, and then its effect is gradually reduced, although it is clearly NMR detectable along the RNA chain. Thus, such specific generation of a charge at a single nucleobase moiety allows us to explore the relative strength of stacking within a single-stranded helix. The pK(a) of 5'-Gp residue from its own deltaH8G in the hexameric RNA 8 is found to be 9.76 +/- 0.01; it, however, varies from 9.65 +/- 0.01 to 10.5 +/- 0.07 along the RNA chain as measured from the other marker protons (H2, H8, H5, and H6) of 9-adeninyl and 1-cytosinyl residues. This nucleobase-dependent modulation of pK(a)s (DeltapK(a) +/- 0.9) of 9-guaninyl obtained from other nucleobases in the hexameric RNA 8 represents a difference of ca. 5.1 kJ mol(-)(1), which has been attributed to the variable strength of electrostatic interactions between the electron densities of the involved atoms in the offset stacked nucleobases as well as with that of the phosphates. The chemical implication of this variable pK(a) for guanin-9-yl deprotonation as obtained from all other marker protons of each nucleotide residue within a ssRNA molecule is that it enables us to experimentally understand the variation of the electronic microenvironment around each constituent nucleobase along the RNA chain in a stepwise manner with very high accuracy without having to make any assumption. This means that the pseudoaromaticity of neighboring 9-adeninyl and next-neighbor nucleobases within a polyanionic sugar-phosphate backbone of a ssRNA can vary from one case to another due to cross-modulation of an electronically coupled pi system by a neighboring nucleobase. This modulation may depend on the sequence context, spatial proximity of the negatively charged phosphates, as well as whether the offset stacking is ON or OFF. The net outcome of this electrostatic interaction between the neighbors is creation of new sequence-dependent hybrid nucleobases in an oligo- or polynucleotide whose properties are unlike the monomeric counterpart, which may have considerable biological implications.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-91150 (URN)10.1021/ja034651h (DOI)12914458 (PubMedID)
Available from: 2003-11-26 Created: 2003-11-26 Last updated: 2017-12-14Bibliographically approved
9. The Nucleobases in Single-stranded DNA are Better Stacked and Yet Their Pseudoaromatic Characters are More Poorly Cross-modulated Than in the RNA Counterparts Due to Variable Tandem Nearest-neighbour Electrostatic Interactions
Open this publication in new window or tab >>The Nucleobases in Single-stranded DNA are Better Stacked and Yet Their Pseudoaromatic Characters are More Poorly Cross-modulated Than in the RNA Counterparts Due to Variable Tandem Nearest-neighbour Electrostatic Interactions
Show others...
In: J. Am. Chem. Soc.Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-91151 (URN)
Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
10. Measurement of nucleobase pKa values in model mononucleotides shows RNA-RNA duplexes to be more stable than DNA-DNA duplexes
Open this publication in new window or tab >>Measurement of nucleobase pKa values in model mononucleotides shows RNA-RNA duplexes to be more stable than DNA-DNA duplexes
Show others...
2004 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 126, no 9, p. 2862-2869Article in journal (Refereed) Published
Abstract [en]

To understand why the RNA-RNA duplexes in general has a higher thermodynamic stability over the corresponding DNA-DNA duplexes, we have measured the pK(a) values of both nucleoside 3',5'-bis-ethyl phosphates [Etp(d/rN)pEt] and nucleoside 3'-ethyl phosphates [(d/rN)pEt] (N = A, G, C, or T/U), modeling as donors and acceptors of base pairs in duplexes. While the 3',5'-bis-phosphates, Etp(d/rN)pEt, mimic the internucleotidic monomeric units of DNA and RNA, in which the stacking contribution is completely absent, the 3'-ethyl phosphates, (d/rN)pEt, mimic the nucleotide at the 5'-end. The pK(a) values of the nucleobase in each of these model nucleoside phosphates have been determined with low pK(a) error (sigma = +/-0.01 to 0.02) by (1)H NMR (at 500 MHz) with 20-33 different pH measurements for each compound. This study has led us to show the following: (1) All monomeric DNA nucleobases are more basic than the corresponding RNA nucleobases in their respective Etp(d/rN)pEt and (d/rN)pEt. (2) The pK(a) values of the monomeric nucleotide blocks as well as Delta pK(a) values between the donor and acceptor can be used to understand the relative base-pairing strength in the oligomeric duplexes in the RNA and DNA series. (3) The Delta G*(pKa) of the donor and acceptor of the base pair in duplexes enables a qualitative dissection of the relative strength of the base-pairing and stacking in the RNA-RNA over the DNA-DNA duplexes. (4) It is also found that the relative contribution of base-pairing strength and nucleobase stacking in RNA-RNA over DNA-DNA is mutually compensating as the % A-T/U content increases or decreases. This interdependency of stacking and hydrogen bonding can be potentially important in the molecular design of the base-pair mimics to expand the alphabet of the genetic code.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-91152 (URN)10.1021/ja0386546 (DOI)14995203 (PubMedID)
Available from: 2003-11-26 Created: 2003-11-26 Last updated: 2017-12-14Bibliographically approved

Open Access in DiVA

fulltext(1461 kB)1934 downloads
File information
File name FULLTEXT01.pdfFile size 1461 kBChecksum SHA-1
aed9eb57301965418b2033d299e2e5dc50371306fb74711312750c6af0b47ebfded67422
Type fulltextMimetype application/pdf
Buy this publication >>

By organisation
Department of Bioorganic Chemistry
Organic Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 1934 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 2409 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf