Signature Peptide MRM Optimization Made Easy for Therapeutic Protein and Peptide Quantification
Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear...
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Transcript of Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear...
![Page 1: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/1.jpg)
Proteins
![Page 2: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/2.jpg)
What is a protein?
• A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.
![Page 3: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/3.jpg)
Protein primary structure
![Page 4: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/4.jpg)
Peptide formation
![Page 5: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/5.jpg)
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
![Page 6: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/6.jpg)
Cells
• muscle
• nerve
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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
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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
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Ligand-binding proteins.
• hemoglobin--transport oxygen from the lungs
• antibodies--bind foreign substances for destruction
![Page 10: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/10.jpg)
The string of amino acids tends to “fold” into a shape.
![Page 11: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/11.jpg)
Hemoglobin structure
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Heart of Steel (Hemoglobin) by Julian Voss-Andreae
![Page 13: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/13.jpg)
Protein views (Triose phosphate isomerase)
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Visualizing proteins
![Page 15: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/15.jpg)
Amino acids
• There are 20 different standard amino acids
• The different amino acids differ in chemical properties.
![Page 16: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/16.jpg)
• 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
![Page 17: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/17.jpg)
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.
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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.
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DNA
• DNA is deoxyribose nucleic acid.
• It occurs as long molecules in a double helix.
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DNA is a long molecule in a double helix
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What makes DNA?
• DNA consists of sequences of nucleotides.
• There are 4 kinds of nucleotide:
• Adenine (A), Cytosine (C), Guanine (G), and Thymine (T)
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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.
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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…
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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.
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Genes
• A gene is a portion of the DNA that tells how to make a protein.
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DNA for beta hemoglobin
• ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAA
![Page 29: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/29.jpg)
• 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
![Page 30: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/30.jpg)
DNA determines the order of amino acids
• ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAA
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Primary structure for beta hemoglobin--the order
• MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
![Page 32: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/32.jpg)
Hemoglobin structure
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How does DNA determine the order of amino acids?
• Three successive nucleotides form a “codon.”
• Different codons stand for different amino acids.
![Page 34: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/34.jpg)
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
![Page 35: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/35.jpg)
DNA for beta hemoglobin
• ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAA
![Page 36: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/36.jpg)
Primary structure for beta hemoglobin
• MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
![Page 37: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/37.jpg)
Hemoglobin structure
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The order of amino acids is important
• Consider what may happen when the “wrong” amino acid is in a certain position.
![Page 39: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/39.jpg)
Primary structure for beta hemoglobin
• MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
![Page 40: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/40.jpg)
Sickle cell anemia beta hemoglobin
• MVHLTPVEKSAVTALWGKVNVDEVGGEALGRLLVVYWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
![Page 41: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/41.jpg)
• 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
![Page 42: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/42.jpg)
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
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A folding of HHPPPPPPPHH
H H P P
P
PP
PPH
H
![Page 44: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/44.jpg)
Another folding of HHPPPPPPPHH
H H P P
P
PPPP
H H
![Page 45: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/45.jpg)
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.
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A folding of HHPPPPPPPHH with energy -2
H H P P
P
PP
PPH
H
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A folding of HHPPPPPPPHH with energy -4
H H P P
P
PPPP
H H
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A folding of HHPPPPPPPHH with ? energy
H H P P
P
PPP
HH P
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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.
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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.
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Indirect Methods
• Statistics of amino acids in known structures
• Neural network models
• Nearest neighbor methods
• Hidden Markov models
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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.
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NMR
• NMR is Nuclear Magnetic Resonance
• Using NMR one can often find the distances between some particular atoms in a protein.
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Distances
• Here d(1,4) is the distance between the first and fourth atoms.A1
A4
A3
A2
d(1,4)
d(2,3)
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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)
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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)
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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)
![Page 58: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/58.jpg)
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)
![Page 59: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/59.jpg)
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)
![Page 60: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/60.jpg)
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.
![Page 61: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/61.jpg)
What is the best folding of
• HPPHPPHPHPPHPHPHHH
• (Careful: answer is on the next slide)
![Page 62: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/62.jpg)
HPPHPPHPHPPHPHPHHH
H
P P
H P
PH
PH
PP
HP
H
P
H
H
H
![Page 63: Proteins. What is a protein? A protein is a molecule consisting of amino acids linked in a linear chain through peptide bonds.](https://reader035.fdocuments.net/reader035/viewer/2022062421/56649ceb5503460f949b5f90/html5/thumbnails/63.jpg)
with energy -11