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Molecular Biology and Biological Chemistry

Molecular Biology and Biological Chemistry

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Molecular Biology and Biological Chemistry

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  1. Molecular Biology and Biological Chemistry The Fundamentals of Bioinformatics Chapter 1

  2. Introduction • The Scale Spectrum • The Genetic Material • Gene Structure and Information Content • Protein Structure and Function • The Nature of Chemical Bonds • Molecular Biology Tools • Genomic Information Content

  3. nano micro macro The Scale Spectrum • Nano • Genes, proteins, genetic networks • Micro • Organ physiology, pharmacokinetics • Macro • Whole body, multi-organism

  4. DNA structure. DNA: Deoxyribose Nucleic Acid History: • 1868 Miescher – discovered nuclein • 1944 Avery – experimental evidence that DNA is constituent of genes. • 1953 Watson&Crick – double helical nature of DNA. “We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.” • 1980 X-ray structure of more than a full turn of DNA.

  5. The Genetic Material • Genes: • the basis of inheritance • A specific sequence of nucleotides.(nt) • Nucleotide bases • 4 types: Guanine(G), Adenine (A), Thymine (T), & Cytosine (C) • Only differ in their ‘Nitrogenous base’ • Alphabet of the ‘Language of Genes’

  6. Five types of bases.

  7. Base Pairings • DNA is highly redundant • Strands are complementary • Permits replication • Base pairings are stable and robust • Only G-C or A-T combinations possible

  8. Complementarity of nucleotide– bases for double stranded helical structure.

  9. Double helical structure of DNA.

  10. Antiparallel Nature of DNA • 5’end of one strand matches 3’ end of other If one strand is 5’-GTATCC-3’ Then other is 3’-CATAGG-5’ Most processes go from 5’ to 3’, so write as: 5’-GGATAC-3’ • Strands are reverse complements • 5’ is ‘upstream’, and 3’ is ‘downstream’

  11. The Genome • Full complement of Genes • Set of chromasomes • DNA chains

  12. The Central Dogma • DNA makes RNA makes Protein • General not universal • Enzymes • Proteins that makes things happen, but are not used up • X_ase RNA-polymerase ribosomes

  13. The Central Dogma (2) • Transcription • RNA construction mediated by RNA-polymerase • One-one correspondence with DNA • G, C, A, and U (Uracil) • Translation • Conversion of nucleotides to amino acids • Ribosomes - complex structure of RNA & protein • Mediates protein synthesis

  14. The Central Dogma (3)

  15. Gene Structure and Information Content • Information formatting and interpretation is very important • Alphabet and punctuation • Same ‘language’ used for both: • Prokaryotes (bacteria) • Eukaryotes (more complex life forms)

  16. Promoter Sequences • Gene Expression • Process of using information in DNA to make RNA molecule then a corresponding protein • Expressing right quantity of protein essential for survival • Two crucial distinctions • Which part of genome is start of a gene • Which genes code for proteins needed at a particular time • Responsibility falls to RNA-polymerase

  17. Promoter sequences (2) • Can’t look for single nucleotide • 1 in 4 chance of appearing at random • General probability of a sequence = (1/4)n • Prokaryotes: 13 nt promoter sequences • 1 in 70 million chance of random appearance • Genome a few million nts long • Datum: 1nt, 6 that are 10 nts upstream & 6 that are 35 nts upstream • Eukaryotes are several orders of magnitude bigger

  18. Promoter Sequences (3) • Two types of Genes: • Structural • Cell structure or metabolism • Regulatory • Production control • Positive regulation • Negative regulation

  19. The Genetic Code • Need way to robustly translate from DNA to Protein • 4 nt alphabet • 20 amino acid (aa) alphabet • Mismatch • Codon (triplet code) • 1&2 nts give < 20 • Each aa coded by a codon • Degeneracy: more than 1 codon per aa = robustness • Stop codon: full stop

  20. The Genetic Code

  21. Open Reading Frames (ORFs) • Start codon: AUG (and methinine) • Reading frame • Established by start codon • Necessary for accurate translation • Mistakes lead to wrong proteins (& premature stops) • Open Reading Frame • Inordinately long reading frame with no stop codon • Proteins 100s of aa long • Random stop: 1 in 20 • Distinguishing feature of prokaryotes and eukaryotes.

  22. Introns and Exons • Messenger RNA - perfect copy of DNA • Introns: locally uninformative sequences in mRNA • Exons: locally informative sequences in mRNA • Splicing: removal of introns, rejoining exons • Spliceosomes: enzymes that do splicing • GT-AG rule (potentially too common) • Checks 6 extra nts • Allows subtle nuances

  23. Introns and Exons (2)

  24. Protein Structure and Function • Proteins are molecular machinery that performs most work in cells • Vast array of tasks • Structure, catalysis, transportation, signalling metabolism … • Highly complex compounds • Primary, secondary, tertiary, quaternary structure.

  25. Primary & Secondary Structure • Primary structure = the linear sequence of amino acids comprising a protein:AGVGTVPMTAYGNDIQYYGQVT… • Secondary structure • Regular patterns of hydrogen bonding in proteins result in two patterns that emerge in nearly every protein structure known: the -helix and the-sheet • The location of direction of these periodic, repeating structures is known as the secondary structure of the protein

  26. Planarity of the peptide bond Psi () – the angle of rotation about the C-C bond. Phi () – the angle of rotation about the N-C bond. The planar bond angles and bond lengths are fixed.

  27. Phi and psi C=O •  =  = 180° is extended conformation •  : C to N–H •  : C=O to C C N–H

  28. The alpha helix     60°

  29. Properties of the alpha helix •     60° • Hydrogen bondsbetween C=O ofresidue n, andNH of residuen+4 • 3.6 residues/turn • 1.5 Å/residue rise • 100°/residue turn

  30. The beta strand (& sheet)    135°  +135°

  31. Properties of beta sheets • Formed of stretches of 5-10 residues in extended conformation • Pleated – each C a bitabove or below the previous • Parallel/aniparallel,contiguous/non-contiguous

  32. Parallel and anti-parallel -sheets Anti-parallel Parallel • Anti-parallel is slightly energetically favored

  33. Molecular Biology Tools • Restriction enzyme digests • Gel electrophoresis • Blotting and hybridization • Cloning • Polymerase chain reaction • DNA sequencing

  34. Genomic Information Content • C-value paradox • No correlation between organism complexity and DNA size • Reassociation Kinetics • Denaturing/renaturing • Cot equation: t0.5 • Junk DNA

  35. … & Finally “There are only 10 types of people in the world: those that understand binary and those that do not” Pete Smith (or Anon)