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Structural proteins provide matrix for bone and connective tissue, giving
structure and form to the human organism. E.g. collagens, elastin, keratin,
histone proteins forming chromatin with DNA.
Exception is proline,
which is heterocyclic,
i.e. the amino group
and the side chain
form a ring.
Side chains define chemical nature and structures of different amino acids
Major groups of amino acids according to their side chains:
1. Monoamino, monocarboxylic acids: they are neutral at pH 7.
Unsubstituted or alkyl amino acids: have alkyl group (hydrocarbon) side
chains and include glycine, alanine, valine, leucine and isoleucine.
(note: Gly has an H+ for an R group)
Proline is unique since it incorporates the alpha amino group in a five-member ring.
(note: proline causes a rigid structure when built into proteins)
Aromatic amino acids: have aromatic groups as side chains and include
phenylalanine, tyrosine and tryptophan.
Sulfur containing amino acids: are cysteine, with a mercapto, and
methionine, with a thioether group.
Two hydroxyl group (alcohol)-containing amino acids are serine and
threonine.
Carboxamide group containing amino acids: have amides in place of the
OH of the carboxylic groups
o Glutamine is amidinated glutamic acid.
o Asparagine is amidinated aspartate acid.
FYI only Figure 3.3. Devlin: Structures of the Common Amino Acids. (Charged forms at pH 7.0.)
Amino Acid
Alanine
Arginine
Asparagine
Aspartate
Asparagine or aspartate
Cysteine
Glycine
Glutamine
Glutamate
Glutamine or glutamate
Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Proline
Serine
Threonine
Tryptophan
Tyrosine
Valine
Ala
Arg
Asn
Asp
Asx
Cys
Gly
Gln
Glu
Glx
His
Ile
Leu
Lys
Met
Phe
Pro
Ser
Thr
Trp
Tyr
Val
A
R
N
D
B
C
G
Q
E
Z
H
I
L
K
M
F
P
S
T
W
Y
V
The reaction of the primary amino group with the primary carboxyl group
of another amino acid yields a dipeptide. The chemical bond formed
between the amino acids is the peptide bond.
The peptide bond has a 50% double bond character.
This means that the electrons are shared among the O
the C and the N;
As a result, rotation does not occur around the peptide
bond (between the C (carbonyl carbon) and the
nitrogen of the peptide bond).
This results in the C=O and the N-H groups lying in a
common plane, while the bonds next to them, between
the C and C, can rotate. This phenomenon becomes
important in protein folding.
Figure 2.2. Lippincott. Formation (A) and isomer structure (B) of a peptide bond.
The sequence of the amino acids in peptides and proteins are listed from
the N-terminal to the C-terminal direction. N-terminal is the free aminogroup of the first amino acid; C-terminal is the free carboxyl group of the
last amino acid.
Name
Function
Pancreatic hormone
involved in regulating
glucose metabolism
Angiotensin
II (horse)
Pressor or hypertensive
peptide; also stimulates
release of aldosterone from
adrenal cortex
Vasodilator peptide
Plasma
bradykinin
(bovine)
Substance P
Neurotransmitter
The NH2-terminal Glu is in the pyro form in which its -COOH is covalently joined to its -NH2 via
amide linkage; the COOH-terminal amino acid is amidated and thus also not free.
b
Cysteine-1 and cysteine-6 are joined to form a disulfide bond structure within the nonapeptide.
c
The Tyr 12 is sulfonated on its phenolic side chain OH.
d
The COOH-terminal amino acid is amidated.
Ionized groups play role in the biological activity of the protein, e.g. in
enzyme-substrate interaction; in hormone-binding to its receptor; etc.
Hydrophobic amino acids, those less soluble in water, such as Leu, Val
and Ile, are mostly in the interior of a protein and help stabilize the
structure.
Polar and charged amino acids are found mostly on the surface and there
interact with each other and water.
When nonpolar amino acids are on the surface they are usually mixed
with polar amino acids to enhance solvation.
When nonpolar amino acid side chains are clustered, they create a
surface that may be a binding site for other proteins or ligands.
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The native conformation is the one that has the lowest Gibbs free energy
kinetically accessible to the polypeptide chain.
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Example 1: Changing the primary structure of a protein brings about the active
conformation.
Insulin is produced as proinsulin by the islet cells of the pancreas. This molecule
has 3 intra-chain disulfide bridges and is physiologically inactive.
When needed, proinsulin is proteolytically modified by proteases in the islet cells
that cleave between residues 30-31 and 65-66 to release a 35 amino acid
residue segment (C-peptide). (C-peptide is used in diagnosing which disease?)
Active insulin contains now two chains, A and B, joined by the same disulfide
bonds as in proinsulin. This molecule is active; can fold into the right
conformation that can bind to cell surface insulin receptors.
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Figure 3.23, Devlin: Primary structures of human proinsulin, insulin and C-peptide.
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Example 2: A single amino acid change in hemoglobin brings about the loss of its
function.
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Secondary structures can form because of the conformation of the peptide bond.
There is no rotation around the peptide bond due to its double bond character.
However, there is rotation allowed between the -carbon and the nitrogen (phi
bond) and the -carbon and the carbonyl carbon (psi bond) of the peptide.
Secondary structures are: -helix
-pleated sheet
-turn
random coil
A. -helical structure
L-amino acids form right-handed alpha helices.
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B. -structures
B/1. -pleated sheet:
Two polypeptide chains or segments of one polypeptide chain are aligned in a
parallel (same direction) or antiparallel (opposite direction) fashion.
-strands appear like pleated sheets.
Hydrogen bonds form between the carbonyl group (C=O) of a peptide bond
of a polypeptide chain and the imino (N-H) group of another peptide bond
from the other polypeptide chain directly next to each other. The side chains
project above and below the pleated sheet like structure.
Figure 2.7. Lippincott. Two polypeptide chains in a -sheet structure conformation (A); Example
of an antiparallel (B) and a parallel (C) sheet structure.
B/2. -turn: When the secondary structural elements, -helix or the -sheet are
disrupted, -turns are frequently formed to let the helix or sheet continue in
another direction. -turns contain 3 amino acid residues (peptide bonds) only,
and stabilized by hydrogen bonds. Proline and glycine are most frequently
found in these structures.
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C. Random coil
Secondary structural segments are connected by random coils (loops). This
gives the basis for the formation of the tertiary structure.
Coils contain non-repetitive but well-defined primary amino acid sequences
and are longer than the -turns.
Many of the coils are functional, found in binding sites, active centers of
proteins. E.g. antigen-binding sites of the immunoglobulins are localized in
random coil segments.
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Example: Hexokinase has two domains. When the substrate (glucose) binds to
this enzyme, the domains move closer, clamp down on the substrate.
Figure 3.32, p. 47, Devlin. Unliganded hexokinase with free glucose (top) and hexokinase with
glucose bound.
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The
primary
protein
structure
contains the properties sufficient to
promote spontaneous protein folding
to its unique conformation.
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Hydrophobic Interaction Forces are the most important for protein folding.
Hydrophobic groups are folded inside the protein to prevent interaction with
water. The presence of large number of hydrophobic residues within a protein
results in the fact that hydrophobic forces are the major contributors to protein
stability.
Hydrogen Bonds
A donor shares a proton with a second atom, called an acceptor.
H bonds help stabilize secondary (as well as tertiary and quaternary)
structures but are less important than hydrophobic interactions for the stability
of the protein.
Electrostatic (ionic) Interactions
Also called ionic or salt bridges, can be repulsive or attractive. They are
formed between a negatively and a positively charged amino acid residue.
Van der Waals-London Dispersion Forces
The weakest interaction, generated by dipole formation by close proximity.
Van der Waals forces are critical for tertiary structure formation. As proteins
fold into tertiary structure, the number of interactions may be in the
thousands.
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Figures 2.10 and 2.11. Lippincott. Interaction of amino acid side chains. A. Hydrophobic
interaction; B. Hydrogen bond and Ionic interaction.
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Lippincott
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