Amino acids

Introduction to Amino acid

• Proteins in human and other

organism are built from 20 alpha
amino acid.
• Alpha amino acid contains chiral
carbon that bound to 4 different
group:
• Hydrogen atom
• R group (side chain)
• Amino group
• Carboxylic acid group
All Amino acids have
chiral carbon except
Glycine, whose side
chain is H.
 Amino Acid configuration

• The majority of AAs

have the (S) absolute
configuration with
exception of cysteine
 Zwitterions
• At normal pH, amino acids exists
in their zwitterions form (dipolar
form)
• Contains both positive and
negative charge
1. Acidic Low pH of 1.0 (high H+)
2. pH increase
3. Basic pH (low H+)
Side chains

• Amino acids differ from one another based on the side chain which vary on:
• Sizes
• Polarity
• Structure and shape
• Charge
• Hydrophobic properties
• Ability to hydrogen bonds
• This variation determines the chemical reactivity
Ionizable amino acids

• Seven of the 20 amino acids have readily ionizable side chains.

• These 7 amino acids can donate or accept protons to facilitate
reactions as well as to form ionic bonds.
• Next table shows typical pKa values for ionization of the side chains of
tyrosine, cysteine, arginine, lysine, histidine, and aspartic and
glutamic acids in proteins.
• Two other groups in proteins—the terminal α-amino group and the
terminal α- carboxyl group—can be ionized, and typical pKa values are
also included in the Table.
• An amino acid with no ionizable R-group would be electrically neutral at
this pH
• This species is called a zwitterions
Why are ionizable amino acids important?
• They can readily exchange hydrogen atoms
• They can interact via ionic bond
 Hydrophobic side chain
(8a.a)

• They have non-polar side chains tend

to pack together instead of interacting
with water
• Isoleucine has another chiral
centre but only the one shown
exist in proteins.
• Phenylalanine contains unreacted
and highly non-polar aromatic ring
• Tyrosine contain aromatic ring with
hydroxyl group which makes it more
reactive and less hydrophobic
• Tryptophan contains an indole
group with NH group make it
slightly reactive
Uncharged polar side chains (5a.a)

• Serine and threonine both have

hydroxyl group which make
them hydrophilic and reactive
• Cysteine is structurally similar to
serine, except it has a thiol group.
Is polar and reactive in forming
disulfide bond (S-S).
• Asparagine and Glutamine
contain polar carboxamide group
which makes them more reactive
than hydrophobic side chains.
 Special side chain

• Glycine is smallest amino acids and

its carbon is a chiral and can fit in
both hydrophobic and hydrophilic
group
• Proline although Proline is
hydrophobic, it is special in that it
contains a side group that is bound to
the a-carbon and the N
• The five membered ring of proline
makes it structurally restrictive,
allowing it to greatly influence the
structure of proteins.
• This unique structure contribute in
the formation of collagen
Charged polar side chain (basic)

• Five amino acids have side chain with

full charge at the normal physiological
pH makes them highly hydrophilic
• Lysine (pKa =10) has relatively long
side chin group that is capped by
primary amino group. At neutral pH the
nitrogen bears a full positive charge.
• Arginine (pKa=12.5) has also
relatively long side chain. The
terminated portion is a group that is
positively charged at a neutral pH.
Histidine (pKa=6.0) contain the imidazole
• Notice that the side chain group is
group, which is an aromatic ring that can be
resonance – stabilized.
protonated around a pH of 6. histidine can
exist in its protonated or deprotonated state at
neutral pH.
 Charged polar side chain (acidic)

• Aspartate at physiological (neutral) pH

this amino acid contain a full negatively
charge on the carboxylic ion group.
• At low pH the carboxylate ion is
protonated. The amino acid is then called
aspartic acid.
• Glutamate (pKa =4) just like aspartate
contains negatively charged carboxylate
group at normal pH
• At low pH the carboxylate group is
protonated, removing the negative charge
and forming glutamic acid.
Peptide bonds

• Proteins are linear polymers of

amino acids that are linked to
one another by covalent bonds
called peptide bonds (or amide
bonds)
 ENERGY
D
• Forward reaction is dehydrolysis
reaction which is thermodynamically
unfavorable. This means that to A B
form a peptide bond we must input
energy.
• So if the dipeptide is energetically
unfavorable why doesn't’t the
reverse reaction occurs
spontaneously? E
D C
• activation energy of the reverse is N
E
simply too high to occur under R A B
normal condition. G
Y

REACTION
PROGRESS
CONCLUSION
• Peptides bonds form via dehydrolysis
• Peptide bond formation is thermodynamically not favorable (require
ATP)
• Peptide bonds are kinetically stable
Proteins
Outline
• Protein primary structure
• Secondary structure
• Tertiary structure and examples
• Quaternary structure
• Hemoglobin
• Protein folding
• Protein confirmation
• Misfolding
 Biology/Chemistry of Protein Structure

Primary Assembly
STRUCTURE

PROCESS
Secondary
Folding

Tertiary
Packing
Quaternary

Interaction
 Primary Structure

• linear
• ordered
• 1 dimensional
• sequence of amino acid
polymer
• written from amino end
to carboxyl end
• a perfectly linear amino
acid polymer is neither
functional nor
energetically favorable
 folding!
N
Ca(R)
• Peptide bonds are resonance stabilized which means they have double-
bond character
• The double bond nature of the peptide bond
• Makes the peptide bond planar
• Prevent any rotation around the peptide bond
Configuration
In the majority of the cases, Trans peptide bonds are energetically more
favorable (less energy is needed to break them up) than Cis because there
is no bumping of atoms

trans-but-2-ene cis-but-2-ene
Φ (phi) = angle of rotation about the single bond between the
nitrogen and ⍺-carbon atom
Ψ (psi) = angle of rotation about the single bond between the
carbonyl carbon atom and ⍺-carbon atom.

These Φ and Ψ rotations ultimately allows the protein to fold into its
three-dimensional structure. Note that not all Φ and Ψ rotations are
possible due to steric hindrance.
Conclusion
• Every protein contains a primary structure that consists
of a unique sequence amino acids linked together by
peptide bonds.
• This sequence of amino acids determines the 3D
structure of the proteins
 Secondary Structure

• Non-linear
• Include the a-helix, the b sheet,
and Turns
• Formed and stabilized by hydrogen
bonding,
• electrostatic and van der Waals
interactions
 Secondary Structure: a Helix

The a helix is stabilized by H-bonds

between backbone carbonyl oxygen and
amide nitrogen atoms that are oriented
parallel to the helix axis.
 Secondary Structure: b Sheets & Turns

In b sheets “pleated sheets”, each b strand

adopts an extended conformation.
ß strands tend to occur in pairs or multiple
copies that interact with one another via H-
bonds.
Carbonyl oxygens and amide nitrogens in the
strands form the H-bonds.
Most ß strands in proteins are 5 to 8 AAs
long.
ß Turns consist of 3-4 amino acids that form
tight bends. Glycine and proline are common
in turns.
Longer connecting segments between ß
strands are called loops.
ß turn
• In parallel beta-sheets the strands all
run in one direction, whereas in
antiparallel sheets they all run in
opposite directions.

• In the arrangement the NH and C=O

groups of an amino acid are one strand
form H bonds with C=O and N-H
group of the opposing amino acid on
the other strand
 Tertiary Structure

Tertiary structure refers to the folded 3D

structure of a protein.
Also known as the native structure or
active conformation.
Formed and stabilized by hydrogen
bonding, covalent (e.g. disulfide)
bonding, hydrophobic packing toward
core and hydrophilic exposure to solvent
The folding of proteins is thought to be
driven by the need to place the most
hydrophobic regions in the interior out
of contact with water.

Keep in mind that most proteins are somewhat flexible and undergo
subtle conformational changes while carrying out their functions.
 Tertiary Structure

• There are several important interactions that are involved

• Hydrophobic interactions:
• Most proteins resist in an aqueous solutions.
• Folding:
1. Hydrophobic side chains will found inside the protein such as alanine,
methionine, tryptophan, phenylalanine, valine, leucine
2. Hydrophilic side chain will found outside the protein such as lysine,
aspartate, arginine
• Van der Waal’s interactions:
• The non-polar amino acids of the protein core interact with one
another via their instantaneous dipole movements. Although these van
der Waal’s forces are relatively weak on an individual base, the
aggregate effect of the many non-polar amino acids creates a
substantial binding effect.
Hydrophobic core and hydrophilic surface
 Other bonds on tertiary structure

• Hydrogen bonds:
• The polar and hydrophilic chains on the surface interact with the
water molecules via hydrogen bonds

• Ionic interactions
• Two oppositely charged side chains can interact via ionic bonds for
instance, lysine and arginine positive charge can form an ionic
bond with aspartate
Quaternary Structure

• non-linear
• 3 dimensional
• globular, and across distinct
amino acid polymers
• formed by hydrogen
bonding, covalent bonding,
hydrophobic packing and
hydrophilic exposure
• favorable, functional
structures occur frequently
and have been categorized.
 Quaternary structure
• The primary structure is the specific sequence of amino acids
• The secondary structure is the spatial arrangement of amino acids found in
close a proximity on the polypeptide chain
• The tertiary structure is the spatial arrangement of amino acids found far
away on the polypeptides
• In some cases large proteins can consist of the two or more polypeptide chains.
Quaternary structure refers to the ways in which these polypeptides interact
with one another.
• A dimer is the two polypeptide that constitute the protein
• Each individual polypeptide is called a subunit
• The subunit held together by non-covalent bonds but can also connect by
covalent bond such as disulfide bridges
• Protein large categories with quaternary structure
• Globular proteins
• Fibrous proteins
Fibrous Proteins
Fibrous proteins, e.g. collagen,
largely involved in structural roles
(found in the bones, muscles, skin).

Keratin is the major structural fibrous

protein to form hair, wool, feathers,
nails, and horns of many kinds of
animals, and has a high concentration
of cysteine
Globular proteins

• These proteins have a wide range of functions and are relatively

spherical in shape. Some example include hemoglobin, insulin, DNA
polymerase, etc.
• Hemoglobin is a tetramer that consists of four individual subunits
• Each subunit is equipped with a heme group that is capable of binding
an oxygen molecule
 Protein Folding
• Occurs in the cytosol • Yields secondary structure
• Involves localized spatial • Cannot be broken down or
interaction among primary denature by typical methods.
structure elements, i.e. the Sustained heat for several
amino acids hours at extremely high
• May or may not involve temperatures (900°F and
chaperone proteins above)
Misfolding
Although they start out as harmless brain proteins, when prions
become misfolded, they turn into contagious pathogens that recruit
any other prions they come into contact with, grouping together in
clumps that damage other cells and eventually cause the brain itself to
break down.
Modification of amino acid
• Proteins are functionally diverse macromolecules. To enhance their
diversity in functions, the twenty different amino acids can be
modified in many different ways.
• Acetyl groups
• Carbonyl groups
• Sugar groups
• Phosphoryl groups
• Cleavage of polypeptides
Hydroxyl Groups:
Collagen the most abundant protein in our body contains proline amino acids that contain hydroxyl
groups. These hydroxyl stabilize the structure.
In a disease called scurvy, a deficiency in vitamin C leads to the inability to produce hydroxyl-proline in
collagen. This leads to a decrease in tissue strength.

Carboxyl Groups:
In protein called prothrombin, the glutamate amino acids contain carboxyl groups. Without these groups
prothrombin cannot work properly and this can lead to hemorrhage.

Sugar Groups:
Many proteins that are destined for the cell membrane or secretion are modified
with sugar groups. These make them more hydrophilic which increase their ability
to interact with other proteins.

Phosphoryl Group:
Epinephrine, a hormone and neurotransmitter, can act on serine and threonine amino acids by
phosphorylating them. These can act as trigger to turn on and off many types of cellular process

Cleavage of polypeptide:
Many proteins in the body are produced in their inactive form. To activate these protein special enzymes
cleave peptide bonds in the inactive proteins, thereby activating them:
• Digestive enzyme(chymotrypsin)
• Blood clotting proteins (fibrin)
• Hormones ( ACTH)