1. Protein structure is conceptually divided into four levels of organization
Primary structure is the amino acid sequence of a protein's polypeptide chain.
Different regions of the sequence form local regular secondary structures, such as alpha helices or beta strands.
The tertiary structure or fold is formed by packing such structural elements into one or several compact globular units called domains.
The final protein may contain several polypeptide chains arranged in a quaternary structure.
By formation of such tertiary and quaternary structure, amino acids far apart in the sequence may be brought close together in three dimensions to form a functional region, an active site.
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Animations:

2. The "handedness" of amino acids
Looking down the H-Ca bond from the hydrogen atom, the L-form has CO, R, and N substituents from Ca going in a clockwise direction. There is a mnemonic rule to remember this; for the L-form the groups read CORN in clockwise direction.
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3. Hydrophobic amino acids
Weak interaction only (van der Waals) with other residues as well as the solvent.
Special attention to
Phenylalanine: aromatic
Methionine: containing inert sulfur; encoded by START codon
Proline: cyclic residue, no free rotation around the Ca-N bond
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4. Charged amino acids - +
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5. Hydrophilic amino acids
Strong interaction (hydrogen bonds) with the solvent and other residues.
Special attention to
Serine, threonine: alcohol group.
Cysteine: containing sulfur as thiol; oxidized by O2 to yield S-S bonds.
Tyrosine, tryptophan: aromatic residues.
Histidine: pK near neutral.
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6. Summary
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7. Hydrophobicity Scales and Plots
Residue
Kyte-Doolittle
Hopp-Woods
Alanine A
1.8
-0.5
Arginine R
-4.5
3.0
Asparagine N
-3.5
0.2
Aspartic acid - D
Cysteine C
2.5
-1.0
Glutamine Q
Glutamic acid - E
Glycine G
-0.4
0.0
Histidine H
-3.2
Isoleucine I
4.5
-1.8
Leucine L
3.8
Lysine K
-3.9
Methionine M
1.9
-1.3
Phenylalanine - F
2.8
- 2.5
Proline P
-1.6
Serine S
-0.8
0.3
Threonine T
-0.7
Tryptophan W
-0.9
-3.4
Tyrosine Y
-2.3
Valine V
4.2
-1.5
Opsin: 349 aa; window=21
7 transmembrane helices
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8. Proteins are built up by amino acids that are linked by peptide bonds to form a polypeptide chain.
Schematic diagram of an amino acid. A central carbon atom (Ca) is attached to an amino group (NH2), a carboxyl group (COOH), a hydrogen atom (H), and a side chain (R).
In a polypeptide chain the carboxyl group of amino acid n has formed a peptide bond, C-N, to the amino group of amino acid n + 1. One water molecule is eliminated in this process. The repeating units, or residues, are divided into main-chain atoms and side chains.
The main-chain part, which is identical in all residues, contains a central Ca atom attached to an NH group, a C'=O group, and an H atom. The side chain R, which is different for different residues, is bound to the Ca atom.
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9. ca-Prot_Enz

10. A polypeptide chain may be viewed as divided into block peptide units
Each peptide unit contains the Ca atom and the C'=O group of residue n as well as the NH group and the Ca atom of residue n + 1. Each such unit is a planar, rigid group with known bond distances and bond angles. R1, R2, and R3 are the side chains attached to the Ca atoms that link the peptide units in the polypeptide chain. The peptide group is planar because the additional electron pair of the C’=O bond is delocalized over the peptide group such that rotation around the C’-N bond is prevented by an energy barrier.
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11. A structural biologist glance at a polypeptide
Cterm
A structural biologist glance at a polypeptide
Each planar peptide unit is rigid and has two degrees of freedom; it can rotate around two bonds, its N--Ca bond and its Ca--C' bond.
The angle of rotation around the N--Ca bond is called phi (f) and that around the Ca--C' bond is called psi (y).
The conformation of the main-chain atoms is therefore determined by the values of these two angles for each amino acid.
Nterm
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12. Allowed combinations of the conformational angles phi and psi.
Since phi (f) and psi (y) refer to rotations of two rigid peptide units around the same Ca atom, most combinations produce steric collisions either between atoms in different peptide groups or between a peptide unit and the side chain attached to Ca. These combinations are therefore not allowed.
Colored areas show sterically allowed regions. The areas labeled a, b, and L correspond to conformational angles found for the usual right-handed a helices, b strands, and left-handed a helices, respectively.
Observed values for all residue types except glycine. Each point represents f and y values for an amino acid residue in a well-refined X-ray structure to high resolution.
Observed values for glycine. Notice that the values include combinations of f and y that are not allowed for other amino acids.
( J. Richardson, Adv. Prot. Chem. 34: , 1981.)
Ramachandran plots
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13. Structure-stabilizing non-covalent bonds
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14. The disulfide bond is usually the end product of air oxidation
2 -CH2SH + 1/2 O2 ↔ -CH2-S-S-CH2 + H2O
Disulfide bonds form between the side chains of two cysteine residues. Two SH groups from cysteine residues, which may be in different parts of the amino acid sequence but adjacent in the three-dimensional structure, are oxidized to form one S-S (disulfide) group.
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15. Intrinsic metal atoms in proteins
The di-iron center of the enzyme ribonucleotide reductase. Two iron atoms form a redox center that produces a free radical in a nearby tyrosine side chain. The iron atoms are bridged by a glutamic acid residue and a negatively charged oxygen atom called a m-oxo bridge. The coordination of the iron atoms is completed by histidine, aspartic acid, and glutamic acid side chains as well as water molecules.
The catalytically active zinc atom in the enzyme alcohol dehydrogenase. The zinc atom is coordinated to the protein by one histidine and two cysteine side chains. During catalysis zinc binds an alcohol molecule in a suitable position for hydride transfer to the coenzyme moiety, a nicotinamide.
[(a) Adapted from P. Nordlund et al., Nature 345: , 1990.]
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16. Folding topology of globular proteins
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17. Intramolecular hydrogen bonds
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18. Breaking H-bonds causes denaturation
Urea (NH2-CO-NH2), a chaotropic agent at high concentrations (2-8 M) breaks H-bonds between protein surface atoms and the aqueous solvent, resulting in the loss of native folding. Its slow removal (e.g., by dialysis) often restores the original fold.
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19. Basic elements of secondary structure
The alpha-helix
Stabilized by hydrogen bonds between the amino –NH and the carbonyl –CO, both belonging to peptide bonds, 4 residues apart on the same sequence fragment.
The beta-sheet
Stabilized similarly by hydrogen bonds but the interacting moieties (i.e., – NH and –CO) are located on different but contiguous beta-strands.
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