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Roadmap

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Proteins perform a vast array of biological functions including: ... Bovine Ribonuclease. Christian Anfinsen, 1957. Disulfide Bonds ... – PowerPoint PPT presentation

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Title: Roadmap


1
Roadmap
  • The topics
  • basic concepts of molecular biology
  • more on Perl
  • overview of the field
  • biological databases and database searching
  • sequence alignments
  • phylogenetics
  • structure prediction
  • microarray data analysis

2
Protein Synthesis
the national health museum
3
Proteins
4
Proteins
  • Proteins perform a vast array of biological
    functions including
  • Transport hemoglobin (delivers O2 to lungs)
  • Mechanical support collagen
  • Storage ferritin (stores iron)
  • Regulation repressor proteins (gene expression)
  • Antibodies immunoglobulin
  • Catalysis SOD (superoxide dismutase)
  • Misfold
  • mad cow disease, Alzheimer's disease,

5
Amino acid composition
  • Basic Amino AcidStructure
  • The side chain, R,varies for each ofthe 20
    amino acids

6
The Peptide Bond
  • Dehydration synthesis
  • Polypeptide with repeating backbone NC? C
    NC? C

7
Side chain properties
  • What make amino acids having different properties
    ?
  • Carbon does not make hydrogen bonds with water
    easily hydrophobic
  • O and N are generally more likely than C to
    h-bond to water hydrophilic
  • The amino acids forms three general groups
  • Hydrophobic
  • Polar
  • Charged (positive/basic negative/acidic)

8
The Hydrophobic Amino Acids
Proline severely limits allowable conformations!
9
The Charged Amino Acids
Krane Raymer
10
The Polar Amino Acids
Krane Raymer
11
More Polar Amino Acids
and
12
Peptidyl polymers
  • A few amino acids in a chain are called a
    polypeptide. A protein is usually composed of 50
    to 400 amino acids.

13
Primary Secondary Structure
  • Primary structure the linear sequence of amino
    acids comprising a protein AGVGTVPMTAYGNDIQYYGQV
    T
  • 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

14
Levels of Protein Structure
  • Secondary structure elements combine to form
    tertiary structure
  • Quaternary structure occurs in multi-enzyme
    complexes
  • Many proteins are active only as homodimers,
    homotetramers, etc.

15
Dihedral angles
16
? Helix
  • Most abundant secondary structure
  • 3.6 amino acids per turn
  • Hydrogen bond formed between every fourth reside
  • Avg length 10 amino acids, or 3 turns
  • Varies from 5 to 40 amino acids

17
? Helix
  • Normally found on the surface of protein cores
  • Interact with aqueous environment
  • Inner facing side has hydrophobic amino acids
  • Outer-facing side has hydrophilic amino acids
  • Every third amino acid tends to be hydrophobic
  • Pattern can be detected computationally
  • Rich in alanine (A), gutamic acid (E), leucine
    (L), and methionine (M)
  • Poor in proline (P), glycine (G), tyrosine (Y),
    and serine (S)

18
? Sheet
19
? Sheet
  • Hydrogen bonds between 5-10 consecutive amino
    acids in one portion of the chain with another
    5-10 farther down the chain
  • Interacting regions may be adjacent with a short
    loop, or far apart with other structures in
    between
  • Directions
  • Same Parallel Sheet
  • Opposite Anti-parallel Sheet
  • Mixed Mixed Sheet
  • Alpha carbons (and R side groups) alternate above
    below the sheet
  • Prediction difficult, due to wide range of ? and
    ? angles

20
Ramachandran Plot (alpha)
21
Ramachandran Plot (beta)
22
Ramachandran Plot
23
Helices and Sheets
24
Loop
  • Regions between ? helices and ? sheets
  • Various lengths and three-dimensional
    configurations
  • Located on surface of the structure
  • Hairpin loops complete turn in the polypeptide
    chain, (anti-parallel ? sheets)
  • More variable sequence structure
  • Tend to have charged and polar amino acids

25
Coil
  • Region of secondary structure that is not a
    helix, sheet, or loop

26
Determining Protein Structure
  • There are O(100,000) distinct proteins in human
    proteome.
  • Two methods for revealing positions of atoms in
    3-D
  • X-Ray Crystallography
  • X-ray diffraction pattern mathematical
    construction
  • Good protein crystal needed, good resolution of
    diffraction needed
  • Nuclear Magnetic Resonance
  • Small proteins only (lt 250 residues)
  • Inter-proton distances geometric constraints

27
Bovine Ribonuclease
Christian Anfinsen, 1957.
28
Disulfide Bonds
  • Two cysteines in close proximity will form a
    covalent bond
  • Disulfide bond, disulfide bridge, or dicysteine
    bond.
  • Significantly stabilizes tertiary structure.

29
(No Transcript)
30
Principles that govern the folding of protein
chains - Christian Anfinsen, Science 1973
31
Ribonuclease
32
Disulfide Bonds
3
15
105
945
10395
33
Levinthals paradox
  • How do proteins find the right conformation out
    of the simply endless number of potential
    three-dimensional forms that it could randomly
    fold into?
  • Consider a 100 residue protein. If each residue
    can take only 3 positions, there are ?
  • possible conformations.
  • If it takes 10-13s to convert from 1 structure to
    another, exhaustive search would take ?
    years!

3100 5 ? 1047
1.6 ? 1027
34
Current Opinion in Structural Biology, 2004, 14,
70-75
35
What determines fold?
  • Anfinsens experiments in 1957 demonstrated that
    proteins can fold spontaneously into their native
    conformations under physiological conditions.
    This implies that primary structure does indeed
    determine folding or 3-D structure.
  • Exceptions exist
  • Chaperone proteins assist folding
  • Abnormally folded Prion proteins can catalyze
    misfolding of normal prion proteins that then
    aggregate

36
Other factors
  • Physical properties of protein that influence
    stability therefore, determine its fold
  • Rigidity of backbone
  • Amino acid interaction with water
  • Hydropathy index for side chains
  • Interactions among amino acids
  • Electrostatic interactions
  • Hydrogen, disulphide bonds
  • Volume constraints

37
Understand protein folding
  • Structure Given a sequence, what tertiary
    structure does it adopt?
  • Global optimization, Monte Carlo, Molecular
    dynamics, Coarse-grained dynamics, etc.
  • Thermodynamics under mutation does the free
    energy of the native state change relative to
    native sequence?
  • MC, MD, Free energy methods, etc.
  • Kinetics how fast does the protein fold? Does a
    different sequence fold faster and why?
  • Lattice Monte Carlo, Molecular dynamics,
    Coarse-grained dynamics

38
CASP changed the landscape
  • Critical Assessment of Structure Prediction
    competition. Even numbered years since 1994
  • Solved, but unpublished structures are posted in
    May, predictions due in September
  • Various categories
  • Relation to existing structures, ab initio,
    homology, fold, etc.
  • Partial vs. Fully automated approaches
  • Produces lots of information about what aspects
    of the problems are hard, and ends arguments
    about test sets.
  • Results showing steady improvement, and the value
    of integrative approaches.
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