Nucleotides and nucleic acids I Biochemistry 302 January...

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Nucleotides and nucleic acids I Biochemistry 302 January 18, 2006

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  • Nucleotides and nucleic acids IBiochemistry 302

    January 18, 2006

  • http://biochem.uvm.edu/courses/kelm/302

    User: studentPW: nucleicacids

  • Central Dogma of Molecular Biology(Cell as a factory analogy)

    DNA = permanent repository which stores master plans

    RNA = temporary repository copyof certain plans Working RNAs (e.g.

    rRNA, snRNA). Adapter RNAs (e.g.

    tRNA, miRNA) Intermediary RNAs (e.g.

    mRNA). Protein = working

    machineryFig. 4.23

  • Basic chemical structure of DNA and RNA (heteropolymers of nucleotides)

    Monomer composition (nucleotide) heterocyclic

    pentose sugar phosphate nitrogenous base

    RNA: polar ribose phosphate backbone

    DNA: polar deoxyribose phosphate backbone (no 2-hydroxyl)

    Nucleotides joined by 3,5- phosphodiester linkages

    Nitrogenous bases side chains

    Lehninger Principles of Biochemistry, 4th ed., Ch 8

  • Major nitrogenous bases found in DNA and/or RNA (purines & pyrimidines)

    DNA: A, G, C, T RNA: A, G, C, U N--glycosyl bond: 1

    carbon of ribose and N9 of Pur base (A, G) or N1 of Pyr base (C, T, U)

    Pur or Pyr base + ribose = nucleoside

    Fig. 4.2

    parent compounds

  • Nucleotide Nomenclature

    DNA

    RNA

  • Chemistry of nucleotide components Phosphate group

    Strong acid pKa ~1 for primary ionization,

    ~6 for secondary

    Purine/Pyrimidine (pKa ~2.4-9.5) Weak tautomeric bases

    Isomers differing in position of H atoms & double bond.

    Less stable imino & enol forms found in special base interactions.

    Conjugated double-bonds Resonance among ring atoms Absorb UV light

    Fig. 4.4Lehninger Principles of Biochemistry, 4th ed., Ch 8

  • Chemical stability of polynucleotides(contribution of the ribose ring)

    Hydrolysis of DNA and RNA is thermodynamically favorable but very slow.

    Acid-labile bond (purine glycosidic linkage in DNA but not RNA

    Base-labile bond (PDE bond in RNA but not DNA)

    Nucleases (endo & exo, specific & non-specific) promote rapid hydrolysis of PDE bonds in DNA or RNA.

    Dehydration-resistant (e.g. DNA in fossils) but water content (level of hydration) affects secondary structure

    Lehninger Principles of Biochemistry, 4th ed., Ch 8

  • DNA and genetics: a historical perspective ~1868 Friedrich Miescher isolates phosphorus-containing

    substance nuclein from nuclei of leukocytes and salmon sperm, noted 2 portions Acidic (DNA), Basic (Protein)

    CW 1860s to 1940s Genetic inheritance dictated by proteins Nucleic acid too simple (4 nucleotides vs ~20 amino acids DNA merely a structural material present in the cell nucleus.

    1944 to 1952 DNA transfer & labeling studies point to DNA as the repository of genetic information.

    Late 1940s Chargaffs rules of DNA composition A = T; G = C; A + G (purines) = C + T (pyrimidines)

    1953 Watson & Crick propose structure of DNA.

  • Hershey-Chase, 1952Avery, MacLeod, and McCarty, 1944

    T2 bacteriophage infection

    Viral T2 32P-DNA (not 35S-protein) transferred to and propagated in E. coli

  • Elucidation of DNA structureFranklin and Wilkins 1953; Kings CollegeWatson and Crick 1953; Cambridge Univ.

    R. Franklin & M. Wilkins X-ray diffraction pattern of wet DNA fibers consistent with regular, repetitive helical 3D structure w/ 2 distinct periodicities. Primary repeat ( 3.4 ) Secondary repeat (34 )

    J. Watson & F. Crick Built best fit model based on X-ray data, Chargaffs rules, DNA chemical composition, & clever deduction. Ten residues/turn (34 ) Helical rise (3.4 , distance betw

    vertically stacked bases Two DNA strands/helix (fiber

    density)R. E. Franklin and R. Gosling (1953) Nature 171:740

    Cross pattern typical of helix

  • Properties of nucleotide bases 3D structure of nucleic acid pH-dependent tautomers

    Adenine and Cytosine (amino form at pH 7) Guanine and Thymine (keto form at pH 7)

    Functional groups (H-bonding) Ring nitrogens Carbonyl groups Exocyclic amino groups

    Highly conjugated resonance Pyrimidines (planar) Purines (nearly planar slight pucker)

    Hydrophobic character Hydrophobic stacking interactions van der Waals interactions between

    uncharged atoms

  • Watson and Crick 1953Intuition: H-bonding between certain baseson opposite strands stabilizes the helix

    Geometric Features: H-bonding between A=T, GC base pairs distance between C-1 atoms the same constant helical diameter

    Bases stacked & slightly offset inside the double helix

    Deoxyribose-phosphate backbone exposed to water

    Pentose ring in C-2 endoconformation (sugar pucker)

    antiparallel strands

    bp stackingand rotation relative to long axis

    H-bonding (different # in A=T vs GC bps)

    ~1.08 nm

    36

    Rise = 0.34 nm

    Fig. 4.10

  • H-bonding pattern in W-C base pairs and numbering convention

    A = T (N6,N1) = (O4,N3)

    Lehninger Principles of Biochemistry, 4th ed., Ch 8

    G C(O6,N1,N2) (N4,N3,O2)

    antiparallel strands

    (H-bond: two electronegative atoms, such as nitrogen and oxygen,

    interacting with the same hydrogen)

  • Other features of Watson-Crick model

    Right handedness (counterclockwise rotation)

    Antiparallel strands Major/minor grooves

    Created by offset base pairing of 2 strands

    Major groove allows direct access to bases

    Minor groove faces ribose backbone

    Base-pairing explains Chargaffs rule A/T or G/C ~1 in organisms with dsDNA genomes.

    van der Waals radius of atoms

    3

    5

    Fig. 4.11

  • Other views of the Watson-Crick model for the structure of DNA

    Because B-DNA is really 10.5 bp/turn.

    Lehninger Principles of Biochemistry, 4th ed., Ch 8

    Ribose and phosphate oxygens are in blue.

    Phosphorus atoms are in yellow. Atoms comprising

    bases are in gray.

  • Were Watson and Crick right?

    Limitations of fiber diffraction studies Fiber heterogeneity Modeling intensive

    (idealized version) Enhanced precision of

    crystallography Atom positions specified Structure of B-DNA more

    distorted than Watson-Crick model

    Bending occurs wherever 4 adenosine residues appear in a row in one strand

    R.E. Dickerson et al. 1983

    DNA Bending

    Fig. 4-16

  • Secondary structural variants (deduced from fiber diffraction and crystal structures)

    B-form DNA fibers prepared under

    high humidity Form found in cells

    A-form (compact) DNA fibers prepared under

    low humidity RNA-RNA and RNA-DNA

    hybrids Z-form (zigzag)

    elongated left-handed DNA alternating C (or 5-meC) &

    G residues in alternating anti and syn glycosyl bond conformation Each structure has 36 bp.

    Z-DNA: deeper narrowminor

    groove

    A-DNA: deeper narrow major

    groove

  • Properties of the three forms of DNA

    Pitch = (Helix rise)(base pairs/turn)

    Lehninger Principles of Biochemistry, 4th ed., Ch 8

  • Structural variation in DNA & dsRNAnucleotide conformation

    Steric constraints restrict rotation about bonds 4 (sugar pucker) and 7 (C-1-N-glycosyl bond) in different DNA structural variants (A, B, Z).

    H

    Lehninger, Principles of Biochemistry, 4th ed., Ch 8

  • Structural variation in DNA & dsRNA-furanose or sugar pucker

    B-DNA A-DNA (or RNA)

    Lehninger Principles of Biochemistry, 4th ed., Ch 8

  • What drives B-DNA into an A-DNA conformation?

    Similarities Helical sense W-C base pairing

    Differences Position of bases with

    respect to helical axis Base tilt Groove width and depth

    (shallower minor groove in A-DNA but deeper major groove)

    11 bp/turn in A-DNA Rise, pitch (repeat), and

    rotation per residue are smaller in A-DNA

    Fig. 4-15

    No H2O


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