Nucleic Acids II

• Nucleotides


  Phosphate esters of nucleosides
• Nucleotides


  • Phosphate groups are attached to free hydroxyl groups on the ribosyl sugar
  • Nucleotides play many roles in biochemistry other than just making up nucleic acids
  • The phosphate groups give the nucleotides overall negative charges at physiological pH, which becomes important in terms of the structure for DNA, compared to the positive charges on the bases
• Nucleic acids structure


  1. Nucleotides are linked via a single phosphate group bridging between two sugar units

  2. The sugar-phosphate groups form the sugar-phosphate backbone of the chain with the bases hanging off it like chains, perpendicular to the backbone
• Directionality of nucleic acid chains


  • The chain runs in a definite direction: all of the 5' groups on the riboses are above the 3'
  • The sequence is conventionally written 5' to 3', left to right
• DNA vs RNA


  • RNA usually occurs in single strands whereas DNA is usually found in a double stranded helix
  • The two strands forming the duplex run in opposite directions

  
• Watson-Crick base pairing


  • AT pair has two hydrogen bonds, GC pair has three
  • The distance between the C1' atoms and the angle between the glycosidic bonds are the same for each pair
  • This isomorphous geometry allows for the construction of a regular DNA framework

  
• Shapes of nucleotide pairs


  • The bases are aromatic rings and are hence planar
  • The hydrogen bonding between the bases ensures that both bases in the pair are in the same plane
  • The sugars are more or less perpendicular to the plane of the bases
• DNA helix formation


  1. The key interactions are between the base pairs which have a tendency to line up one above the other

  2. This gives DNA its helical shape

  3. The sugar-phosphate backbone is quite flexible and hence it does not give DNA its helical shape

  
• π-stacking of bases


  • Aromatic rings have extensive, delocalised systems of electrons in p-orbitals above and below the plane of the ring
  • These orbitals can form energetically favourable overlaps with other p-orbitals, sharing electrons, in adjacent rings - this is called π-stacking and gives a low energy conformation
  • Due to the constraint of the sugar-phosphate backbone, this interaction ends up with the formation of the double helix
• DNA shapes


  • The DNA will have the bases more or less in a plane perpendicular to the long axis of the helix
  • The exact shape of the DNA strand will depend on its chemical environment and the sequence of bases
  • The negative charges on the backbone phosphate will repel and stretch the strand
  • If the bases are not all in the same plane but tilted to one another, then the strand will bend

  
• Major and minor grooves


  • As the double helix bends, two grooves are formed: the major and minor grooves, which are important in terms of drug discovery as a drug will have a tendency to bind either in the major groove or the minor groove
  • Each groove is a different size, shape and contains a different chemical environment

  
• Packaging of DNA


  • DNA is not just found as a straight chain but also as circles so it can fit in the nucleus
  • Circular DNA can be supercoiled — like twisting a rubber band
  • Human DNA contains 7.8 × 10^9 base pairs which gives it a length of about 2m
  • DNA must be efficiently packaged to fit into the cellular nucleus
  • Proteins called histones neutralise the negative charges on the phosphate groups and the DNA can wrap around them
• RNA structure


  RNA adopts a single stranded structure which can form hairpin turns and loops. It can fold back on itself and form double helices along with a variety of other structural features

  
• A biologically important species is the DNA-RNA hybrid helix, which has a strand of DNA in a double helix with a strand of RNA

  
• DNA as a drug target


  • Antivirals: Drugs have been developed which prevent the synthesis of viral DNA or RNA
  • Anticancer: Drugs have been developed which either damage or alter the structure of DNA so it can no longer function. This will damage cancer cells faster than slower growing normal tissue
  • Gene therapy: By the introduction of small pieces of DNA into a cell then a protein can be synthesised which would not normally be present in that cell