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Proteins. What is a protein?. A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds. Protein primary structure. Peptide formation. There are many kinds of proteins. Structural--determine shape and function of cells - PowerPoint PPT Presentation
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What is a protein?
• A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.
There are many kinds of proteins.
• Structural--determine shape and function of cells
• Enzymes--speed up chemical reactions
• Ligand-binding--bind small molecules and transport them to other locations
Structural proteins
• collagen -- in connective tissue such as cartilage
• elastin -- in connective tissue such as cartilage
• keratin--in hair and nails• actin -- in muscle• myosin -- in muscle to generate mechanical
forces
Enzymes
• glucose isomerase--convert glucose into fructose
• rennin--make cheese• cellulase--break down cellulose into sugars to
make ethanol• amylase--detergent for machine dish washing
Ligand-binding proteins.
• hemoglobin--transport oxygen from the lungs
• antibodies--bind foreign substances for destruction
Amino acids
• There are 20 different standard amino acids
• The different amino acids differ in chemical properties.
• Amino Acid 3-Letter 1-Letter Polarity Acidity Hydrophobicity index• Alanine Ala A nonpolar neutral 1.8• Arginine Arg R polar basic (s) -4.5• Asparagine Asn N polar neutral -3.5• Aspartic acid Asp D polar acidic -3.5• Cysteine Cys C nonpolar neutral 2.5• Glutamic acid Glu E polar acidic -3.5• Glutamine Gln Q polar neutral -3.5• Glycine Gly G nonpolar neutral -0.4• Histidine His H polar basic (w) -3.2• Isoleucine Ile I nonpolar neutral 4.5• Leucine Leu L nonpolar neutral 3.8• Lysine Lys K polar basic -3.9• Methionine Met M nonpolar neutral 1.9• Phenylalanine Phe F nonpolar neutral 2.8• Proline Pro P nonpolar neutral -1.6• Serine Ser S polar neutral -0.8• Threonine Thr T polar neutral -0.7• Tryptophan Trp W nonpolar neutral -0.9• Tyrosine Tyr Y polar neutral -1.3• Valine Val V nonpolar neutral 4.2
Hydrophobicity index.
• The larger the index, the stronger the tendency to be internal in the protein; the lower the index, the stronger the tendency to appear near the protein surface.
• Amino acids with high index are called hydrophobic; with low index are called hydrophilic.
What is the shape of the protein?
• This is the “protein folding problem.”
• The geometry and chemistry of the parts of the protein determine how it behaves in the cell.
What makes DNA?
• DNA consists of sequences of nucleotides.
• There are 4 kinds of nucleotide:
• Adenine (A), Cytosine (C), Guanine (G), and Thymine (T)
Matching
• Each A has weak (“hydrogen”) bonds with T on the other chain.
• Each C has weak (“hydrogen”) bonds with G on the other chain.
A single chain carries the information
• For example, the two strings might be
ACGGTCAG
TGCCAGTC
• Hence all the information is in the order of A, C, G, T in one of the chains.
• We write DNA as a (long) string of A, C, G, T for example AGGCTACATAG…
Human DNA
• Humans have 46 chromosomes.
• Each chromosome is essentially a double helix of DNA, with variable numbers of nucleotides, from 50,000,000 to 250,000,000 base pairs.
• There are a total of about 2,860,000,000 nucleotide pairs.
DNA for beta hemoglobin
• ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAA
• Amino Acid 3-Letter 1-Letter Polarity Acidity Hydrophobicity index• Alanine Ala A nonpolar neutral 1.8• Arginine Arg R polar basic (s) -4.5• Asparagine Asn N polar neutral -3.5• Aspartic acid Asp D polar acidic -3.5• Cysteine Cys C nonpolar neutral 2.5• Glutamic acid Glu E polar acidic -3.5• Glutamine Gln Q polar neutral -3.5• Glycine Gly G nonpolar neutral -0.4• Histidine His H polar basic (w) -3.2• Isoleucine Ile I nonpolar neutral 4.5• Leucine Leu L nonpolar neutral 3.8• Lysine Lys K polar basic -3.9• Methionine Met M nonpolar neutral 1.9• Phenylalanine Phe F nonpolar neutral 2.8• Proline Pro P nonpolar neutral -1.6• Serine Ser S polar neutral -0.8• Threonine Thr T polar neutral -0.7• Tryptophan Trp W nonpolar neutral -0.9• Tyrosine Tyr Y polar neutral -1.3• Valine Val V nonpolar neutral 4.2
DNA determines the order of amino acids
• ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAA
Primary structure for beta hemoglobin--the order
• MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
How does DNA determine the order of amino acids?
• Three successive nucleotides form a “codon.”
• Different codons stand for different amino acids.
Translating codons• Ala/A GCT, GCC, GCA, GCG Leu/L TTA, TTG, CTT, CTC, CTA, CTG• Arg/R CGT, CGC, CGA, CGG, AGA, AGG Lys/K AAA, AAG• Asn/N AAT, AAC Met/M ATG• Asp/D GAT, GAC Phe/F TTT, TTC• Cys/C TGT, TGC Pro/P CCT, CCC, CCA, CCG• Gln/Q CAA, CAG Ser/S TCT, TCC, TCA, TCG, AGT, AGC• Glu/E GAA, GAG Thr/T ACT, ACC, ACA, ACG• Gly/G GGT, GGC, GGA, GGG Trp/W TGG• His/H CAT, CAC Tyr/Y TAT, TAC• Ile/I ATT, ATC, ATA Val/V GTT, GTC, GTA, GTG• START ATG STOP TAG, TGA, TAA
DNA for beta hemoglobin
• ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAA
Primary structure for beta hemoglobin
• MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
The order of amino acids is important
• Consider what may happen when the “wrong” amino acid is in a certain position.
Primary structure for beta hemoglobin
• MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
Sickle cell anemia beta hemoglobin
• MVHLTPVEKSAVTALWGKVNVDEVGGEALGRLLVVYWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
• Amino Acid 3-Letter 1-Letter Polarity Acidity Hydrophobicity index• Alanine Ala A nonpolar neutral 1.8• Arginine Arg R polar basic (s) -4.5• Asparagine Asn N polar neutral -3.5• Aspartic acid Asp D polar acidic -3.5• Cysteine Cys C nonpolar neutral 2.5• Glutamic acid Glu E polar acidic -3.5• Glutamine Gln Q polar neutral -3.5• Glycine Gly G nonpolar neutral -0.4• Histidine His H polar basic (w) -3.2• Isoleucine Ile I nonpolar neutral 4.5• Leucine Leu L nonpolar neutral 3.8• Lysine Lys K polar basic -3.9• Methionine Met M nonpolar neutral 1.9• Phenylalanine Phe F nonpolar neutral 2.8• Proline Pro P nonpolar neutral -1.6• Serine Ser S polar neutral -0.8• Threonine Thr T polar neutral -0.7• Tryptophan Trp W nonpolar neutral -0.9• Tyrosine Tyr Y polar neutral -1.3• Valine Val V nonpolar neutral 4.2
Simple model
• Pretend there are only 2 kinds of amino acid--H and P.
• H stands for “hydrophobic”.
• Pretend that they must be placed on a grid.
• Example: HHPPPPPPPHH
Energy
• HH has energy -1.
• PP has energy 0.
• HP has energy 0.
• PH has energy 0.
• The protein folds so as to minimize the energy.
The real problem
• There are 20 amino acids.
• Pairs have different energies.
• Typically a protein has about 100 amino acids.
• The protein is in 3 dimensions.
• It does not need to be on a grid.
• It must be worked on a computer.
The Direct Approach
• Write down a formula for the energy E, taking into account the (variable) locations of all amino acids, all charges and electrostatic attractions and repulsions, and all constraints.
• Minimize E.
Indirect Methods
• Statistics of amino acids in known structures
• Neural network models
• Nearest neighbor methods
• Hidden Markov models
Does a method work?
• We want to be able to check some answers, to see whether a method appears to work.
• Professor Zhijun Wu works on some problems related to this.
NMR
• NMR is Nuclear Magnetic Resonance
• Using NMR one can often find the distances between some particular atoms in a protein.
Distances
• Here d(1,4) is the distance between the first and fourth atoms.A1
A4
A3
A2
d(1,4)
d(2,3)
Locations
• A1 is at (x11, x12, x13).• A2 is at (x21, x22, x23).• A3 is at (x31, x32, x33).• A4 is at (x41, x42, x43).
• Once you know all the locations, you know the shape of the protein.
A1
A4
A3
A2
d(1,4)
d(2,3)
Position Matrix
• Form the matrix X
x11 x12 x13
x21 x22 x23
x31 x32 x33
x41 x42 x43
A1
A4
A3
A2
d(1,4)
d(2,3)
Matrix Equation
• It turns out that
X XT = D where D is a matrix that can be obtained just using all the numbers d(i,j).
A1
A4
A3
A2
d(1,4)
d(2,3)
The matrix D
• If there are n atoms and the last is at the origin, then the entry of D in the ith row and jth column is
(d(i,n)2 - d(i,j)2 + d(j,n)2) / 2
A1
A4
A3
A2
d(1,4)
d(2,3)
Solving the matrix equation
• Professor Zhijun Wu studies ways to solve such matrix equations rapidly.A1
A4
A3
A2
d(1,4)
d(2,3)
Energy
• HH has energy -1.
• PP has energy 0.
• HP has energy 0.
• PH has energy 0.
• The protein folds so as to minimize the energy.