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AA & Genetic Code

AA & Genetic Code. DNA Bases. R. Y. W. M. K. B. A T G C. A T G C. A T G C. A T G C. s. N. H. V. D. A T G C. A T G C. A T G C. A T G C.

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AA & Genetic Code

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  1. AA & Genetic Code

  2. DNA Bases R Y W M K B A T G C A T G C A T G C A T G C s N H V D A T G C A T G C A T G C A T G C

  3. Models of nucleotide substitution transition A G Purine => transversion transversion T C Pyrimidine => transition

  4. Jukes-Cantor (JC) Kimura 2P Kimura

  5. Point Mutation (Substitution) • Point mutation – simplest form of mutation and occurs all over DNA sequences • Transition – mutation within purine (A,G) or pyrimidine (C,T/U) • Transversion – mutation between nt groups • Effects depend on where mutations occur • Non-coding region – no effect on proteins, and neutral • But may have significant effects if occurring in control region • Coding region • Synonymous substitution when a mutation does not change AA • Non-synonymous • AA is replaced by another • stop codon is introduced

  6. Other Mutations • Indel mutation • Small indels of a single base of a few bases are frequent • Particularly frequent with repeated sequences • GCGC…: insertion of extra GC or deletion cause slight slippage • CAG repeated region in huntingtin protein can expand, causing Huntington’s disease • Indels can cause frame shift, if indels are not multiples of three • Gene inversion • Whole genes are copied to offspring in reverse direction • Translocation • Whole genes can be deleted from one genome and inserted into another

  7. Amino Acids • General structure of amino acids • an amino group • a carboxyl group • α-carbon bonded to a hydrogen and a side-chain group, R • R determines the identity of particular amino acid • R: large white and gray • C: black • Nitrogen: blue • Oxygen: red • Hydrogen: white

  8. AA Groups • Classification of R groups • Polar/nonpolar • Polar share electron bonds unequally • O-H bond is polar: O is more electro-negative and bonding electrons are closer to O • C-H is nonpolar • Acidic/basic

  9. Group 1: Nonpolar (hydrophobic) • Sometimes, Gly (G) is included because C-H bond is nonpolar

  10. Group 2: Polar • Side chains are electronically neutral (uncharged) • Ser (S), Thr (T), Cys (C), Asn (N), Gln (Q), Try (Y) • Asn (N) and Gln (Q) are consider derivatives of group 3 Asp (D) and Glu (E)

  11. Group 3: Acidic • Side chains have carboxyl group • Asp (D) and Glu (E) • Side chains are negatively charged

  12. Group 4: Basic • Side chain is positively charged • His (H), Lys (K), Arg (R)

  13. Physico-Chemical Properties • Physico-chemical properties of AA determine protein structures • bioinformatics can be used via a pattern recognition • Properties • (1) Size in volume • Volume occupied by side groups is important (also for molecular evolution), and difficult to substitute a large AA for a small one • Van der Waals radius (volume until atoms are pushed to repulsion) is used to measure the volume of the sphere (in Å3) • W has 3.4 times the volume of G

  14. (2) Partial Vol. • Measure expanded volume in solution when dissolved • (3) Bulkiness • The ratio of side chain volume to its length • Measure of average cross-sectional area of the side chain • Relevant to protein folding • (4) Polarity index • Electrostatic force acting on its surrounding at a distance of 10 Å • (5) pH of isoelectric point of AA (pI) • Acidic Asp and Glu have pI in 2-3: negatively charged at neutral pH due to ionization of COOH group to COO- -- need to put them in an acid solution to shift equilibrium and balance this charge (side chain is charged +) • Basic (Arg, Lys and His) has pI >7 (charged -) • All others have uncharged side chains (pl. in 5-6)

  15. (6) Hydrophobicity • When molecules are dissolved in water, hydrogen-bonded structure is disrupted • Polar AA residues can form hydrogen bonds with water –hydrophilic • Non-polar that cannot form the bonds – hydrophobic • Polar disrupts the structure less than non-polar • Polar is usually at the exterior of a structure, non-polar, interior • Hydrophobicity (hydropathy) scale: estimate of difference in free energy of AA when buried in hydrophobic environment of the interior of a protein in water solution (+ for hydrophobic – costs free energy to take residue out of protein and put it in water) • (7) Surface area • Surface area of AA exposed (accessible) to water in an unfolded peptide chain and become buried when the chain folds • Relevant to protein folding • (8) Fraction of area • Fraction of the accessible surface area that is buried in the interor in a set of known crystal structures • Hydrophobic residues have a larger fraction

  16. Red: acidic Orange: basic Green: polar Yellow: non-polar

  17. “Universal” Genetic Code

  18. Genetic Code 2

  19. Properties • Purine (A,G) is heavier than Pyrimidine (C,T) • Transition within a type (Purines or Pyrimidines) is more likely than Translation between types • All AAs have more than one codon, except for Met and Trp • Codons for an AA are clustered • Two codons for an AA – same in the first 2 positions and differ only by transition at the 3rd position • Four codons – differ only in the 3rd position • Six codons – form one four-codon box and one two-codon box

  20. Genetic Code X X X X • Degeneracy is controlled by GC content of codons • G-C binding is stronger • First two bases (doublets) are GC – form four codon boxes (red X) • Doublets are AU – split boxes (blue X) • Doublets are mixed X X X X Purine • 2nd base is pyrimidine – four codon boxes, split otherwise • Larger purine at the 2nd position reduces binding at the 3rd position • A doublet forms a four-codon box, its ‘conjugate’ forms a split box • Conjugate – opposite size and opposite number of hydrogen bonds; A-C and G-U are conjugates

  21. Genetic Code • Five most hydrophobic – Phe, Leu, Ile, Met, Val • U at the 2nd position • Three most similar – Leu, Ile, Val • Single-base mutation at 1st position • Six most hydrophilic – His,Gln,Asn,Lys,Asp, Glu • A at the 2nd position • (Tyr is hydrophobic and has A in 2nd position)

  22. Evolution of Genetic Code • From what the current Genetic Code became stable ? • Robin Knight • www.cs.uml.edu/~kim/580/99_knight.pdf

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