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Some Aspects of Physicochemical Properties of DNA and RNA
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is based on nine research publications (I – IX) on structure and reactivity of RNA vis-à-vis DNA. The DNA and RNA are made of flexible pentose sugar units, polyelectrolytic phosphodiester backbone, and heterocyclic nucleobases. DNA stores our genetic code, whereas RNA is involved both in protein biosynthesis and catalysis. Various ligand-binding and recognition properties of DNA/RNA are mediated through inter- and intra-molecular H-bonding and stacking interactions, beside hydration, van der Waal and London dispersion forces. In this work the pH dependant chemical shift, pKa values of 2'-OH group as well as those the nucleobases in different sequence context, alkaline hydrolysis of the internucleotidic phosphodiester bonds and analysis of NOESY footprints along with NMR constrained molecular dynamics simulation were used as tools to explore and understand the physico-chemical behavior of various nucleic acid sequences, and the forces involved in their self-assembly process. Papers I – II showed that the ionization of 2'-OH group is nucleobase-dependant. Paper III showed that the chemical characters of internucleotidic phosphate are non-identical in RNA compared to that of DNA. Papers IV – VI show that variable intramolecular electrostatic interactions between electronically coupled nearest neighbor nucleobases in a ssRNA can modulate their respective pseudoaromatic character, and result in creation of a unique set of aglycons with unique properties depending on propensity and geometry of nearest neighbor interaction. Paper VII showed that the cross-modulation of the pseudoaromatic character of nucleobases by the nearest neighbor is sequence-dependant in nature in oligonucleotides. Paper VIII showed that the purine-rich hexameric ssDNA and ssRNA retain the right-handed helical structure (B-type in ssDNA and A-type in ssRNA) in the single-stranded form even in absence of intermolecular hydrogen bonding. The directionality of stacking geometry however differs in ssDNA compared to ssRNA. In ssDNA the relatively electron-rich imidazole stacks above the electron-deficient pyrimidine in the 5' to 3' direction, in contradistinction, the pyrimidine stacks above the imidazole in the 5' to 3' direction in ssRNA. Paper IX showed that the pKa values of the nucleobases in monomeric nucleotides can be used to show that a RNA-RNA duplex is more stable than a DNA-DNA duplex. The dissection of the relative strength of base-pairing and stacking showed that the relative contribution of former compared to that of the latter in an RNA-RNA over the corresponding DNA-DNA duplexes decreases with the increasing content of A-T/U base pairs in a sequence.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2006. , p. 74
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 164
Keywords [en]
Bioorganic chemistry, nucleic acids, hydrogen-bonding, stacking, single-stranded, NMR, molecular dynamics
Keywords [sv]
Bioorganisk kemi
Identifiers
URN: urn:nbn:se:uu:diva-6741ISBN: 91-554-6518-8 (print)OAI: oai:DiVA.org:uu-6741DiVA, id: diva2:168035
Public defence
2006-04-29, Room C10301 (floor 3), Biomedical Center, Uppsala, 12:00
Opponent
Supervisors
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2013-10-25Bibliographically approved
List of papers
1. The pKa’s of 2'-Hydroxyl Group in Nucleosides and Nucleotides
Open this publication in new window or tab >>The pKa’s of 2'-Hydroxyl Group in Nucleosides and Nucleotides
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2001 In: J. Am. Chem. Soc., Vol. 123, p. 2893-2894Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-94240 (URN)
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2014-03-03Bibliographically approved
2. The pKa of the Internucleotidic 2'-Hydroxyl Group in Diribonucleoside (3'→5') Monophosphates
Open this publication in new window or tab >>The pKa of the Internucleotidic 2'-Hydroxyl Group in Diribonucleoside (3'→5') Monophosphates
2003 In: J. Org. Chem., Vol. 68, p. 1906-1910Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-94241 (URN)
Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved
3. Non-identical electronic characters of the internucleotidic pohosphates in RNA modulate the chemical reactivity of the phosphodiester bonds
Open this publication in new window or tab >>Non-identical electronic characters of the internucleotidic pohosphates in RNA modulate the chemical reactivity of the phosphodiester bonds
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2006 In: Org. Biomol. Chem., Vol. 4, p. 928-941Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-94242 (URN)
Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved
4. 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, p. 13722-13730Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-94243 (URN)
Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved
5. Tandem Electrostatic Effect from the First to the Third Aglycon in the Trimeric RNA Owing to the Nearest-Neighbor Interaction
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 Interaction
2003 In: J. Am. Chem. Soc, Vol. 125, p. 2094-2100Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-94244 (URN)
Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved
6. 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
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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
7. Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA
Open this publication in new window or tab >>Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA
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2004 In: J. Am. Chem. Soc., Vol. 126, p. 8674-8681Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-94246 (URN)
Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved
8. Single-Stranded Adenine-Rich DNA and RNA Retain Structural Characteristics of Their Respective Double-Stranded Conformations and Show Directional Differences in Stacking Pattern
Open this publication in new window or tab >>Single-Stranded Adenine-Rich DNA and RNA Retain Structural Characteristics of Their Respective Double-Stranded Conformations and Show Directional Differences in Stacking Pattern
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2004 In: Biochemistry, Vol. 43, p. 15996-16010Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-94247 (URN)
Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved
9. 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
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2004 In: J. Am. Chem. Soc., Vol. 126, p. 2862-2869Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-94248 (URN)
Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved

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