Protein Structure and
Function
• Modern cells, such as those that make
up your body, produce tens of thousands
of distinct proteins.
• Most of these molecules are composed
of just 20 different building blocks, called
amino acids.
• All 20 of these building blocks share a
common core structure.
The charges on these functional
groups are important for two reasons:
(1) They help amino acids stay in
solution, where they can interact with
one another and with other solutes.
(2) they affect the amino acid’s
chemical reactivity.
Amino acid R-groups can be grouped
into three general types:
1. charged, which includes acidic and
basic
2. uncharged polar
3. nonpolar
• Amino acids link to one another to form
proteins. Proteins are macromolecules—large
molecules made up of smaller molecular subunits
joined together. In general, a molecular subunit
used to build a macromolecule is called a
monomer.
• When a large number of monomers are bonded
together, the resulting structure is called a
polymer.
• The process of linking monomers together is
called polymerization.
• Monomers polymerize through condensation
reactions, also known as dehydration reactions.
These reactions are aptly named because the
newly formed bond results in the loss of a water
molecule.
• The reverse reaction, called hydrolysis,
breaks polymers apart by adding a water
molecule. The water molecule reacts with the
bond linking the monomers, separating one
monomer from the polymer chain.
Amino acids polymerize when a bond forms between
the carboxyl group of one amino acid and the amino
group of another. The C-N covalent bond that results
from this condensation reaction is called a peptide
bond.
• Peptide bonds are unusually stable. This is
because a pair of valence electrons on the
nitrogen is partially shared in the C-N bond.
• The degree of electron sharing is great
enough that peptide bonds actually have
some of the characteristics of a double bond.
• For example, the peptide bond is planar,
limiting the movement of the atoms
participating in the peptide bond.
R-group orientation: The side chains of each
residue extend out from the backbone, making it
possible for them to interact with each other and
with water.
Directionality: There is an amino group (-NH3+)
on one end of the backbone and a carboxyl
group (-COO-) on the other. The end of the
residue sequence that has the free amino group
is called the N-terminus, or amino- terminus,
and the end with the free carboxyl group is called
the C-terminus, or carboxy-terminus.
Flexibility: Although the peptide bond itself cannot
rotate because of its double-bond nature, the single
bonds on either side of the peptide bond can rotate.
As a result, the structure as a whole is flexible.
• Generally, when fewer than 50 amino
acids are linked together in this way, the
resulting polymer is called an
oligopeptide (“few-peptides”) or simply
a peptide.
• Polymers that contain 50 or more
amino acids are called polypeptides.
No matter how large or complex a
protein may be, its underlying
structure can be categorized into just
four basic levels of organization.
1. Primary structure
2. Secondary structure
3. Tertiary structure
4. Quaternary structure
• Each protein has a unique sequence
of amino acids. That simple conclusion
was the culmination of 12 years of
study by Frederick Sanger and co-
workers during the 1940s and 1950s.
• Biochemists refer to the unique
sequence of amino acids in a protein
as its primary structure.
With 20 types of amino acids available and
chain lengths of up to tens of thousands of
amino acid residues, the number of primary
structures that are possible is practically
limitless.
There may, in fact, be 20n different
combinations of amino acid residues for a
polymer with a given length of n. For
example, a chain of just 10 amino acids has
2010 possible sequences. This is over 10,000
billion variations.
Why is the order and type of
residues in the primary structure
of a protein important?
In some cases, even a single
change in the sequence of amino
acids can cause striking changes in
the way the protein as a whole
behaves.
Eg. Hemoglobin, an oxygen-binding protein in human red
blood cells.
• In some individuals, the polypeptide sequences that
make up hemoglobin has a valine instead of a glutamate
at the 6th position.
• Valine and glutamate have radically different side
chains.
• The change in R-group produces hemoglobin molecules
that stick to one another and form fibers when oxygen
concentrations in the blood are low. Red blood cells that
carry these fibers adopt a sickle-like shape.
Hydrogen bonding between sections of the
same backbone is possible only when a
polypeptide bends in a way that puts C=O and
N-H groups close together.
1. an 𝛂-helix (alpha-helix), in which the
polypeptide’s backbone is coiled.
2. a 𝛃-pleated sheet (beta-pleated sheet), in
which segments of a peptide chain bend 180°
and then fold in the same plane.
• A protein’s distinctive three-
dimensional shape, or tertiary
structure, results from interactions
between residues that are brought
together as the chain bends and folds.
• Tertiary structures form using a variety
of bonds and interactions between R-
groups or between R-groups and the
backbone.
1. Hydrogen bonding
2. Hydrophobic interactions
In an aqueous solution, water molecules interact with
the hydrophilic polar side chains of a polypeptide,
forcing the hydrophobic nonpolar side chains to
coalesce into globular masses.
• When these non polar R-groups come together, the
surrounding water molecules form more hydrogen
bonds with each other and the polar residues on the
surface of the protein, increasing the stability of their
own interactions.
3. Van der Waals interactions
Once hydrophobic side chains are close to one another,
their association is further stabilized by electrical
attractions known as van der Waals interactions.
• These weak attractions occur because the constant
motion of electrons gives molecules a tiny asymmetry
in charge that changes with time.
• If nonpolar molecules get extremely close to each
other, the minute partial charge on one molecule
induces an opposite partial charge in the nearby
molecule and causes an attraction.
4. Covalent bonding
Covalent bonds can form between the side chains
of two cysteines through a reaction between the
sulfhydryl groups. These disulfide (“two-sulfur”)
bonds are frequently referred to as bridges,
because they create strong links between distinct
regions of the same polypeptide.
5. Ionic bonding
Ionic bonds may form between groups that have
full and opposing charges, such as the ionized
acidic and basic side chains.
• The first three levels of protein structure involve
single polypeptides.
• But some proteins contain multiple
polypeptides that interact to form a single
functional structure. The combination of
polypeptides, referred to as subunits, gives some
proteins quaternary structure.
• The individual polypeptides are held together by
the same types of bonds and interactions found
in the tertiary level of structure.
If you were able to synthesize one of the
polypeptides in hemoglobin from individual amino
acids, and you then placed the resulting chain in an
aqueous solution, it would spontaneously fold into
the shape of the tertiary structure.
• Folding does tend to be spontaneous because the
chemical bonds and interactions that occur release
enough energy to overcome the decrease in
entropy.
• The folded molecule has less potential energy and
is thus more stable than the unfolded molecule.
• Cells contain special proteins called
molecular chaperones that can facilitate
protein folding.
• Many molecular chaperones belong to
a family of molecules called the heat-
shock proteins, because they are
produced in large quantities after cells
experience the denaturing effects of high
temperatures.
• Chaperones recognize unfolded
proteins by binding to hydrophobic
patches that are not normally exposed
when the proteins are folded properly.
• This interaction prevents the
unfolded proteins from clumping
together, allowing them to fold into
the shape specified by their primary
sequence.
• In 1982, Stanley Prusiner published
what may be the most surprising result
to emerge from research on protein
folding:
Certain normal proteins can be
induced to fold into infectious,
disease-causing agents. These proteins
are called prions , or proteinaceous
infectious particles.
• Infectious prions are alternately folded forms of
normal proteins that are present in healthy
individuals. These infectious and normal proteins
do not differ in their primary structure, but their
shapes are radically different.
• Infectious prions propagate by binding to normal
prions and inducing conformational changes that
cause them to adopt the alternate, infectious
shape. This shape change stabilizes the
interactions between prion proteins, resulting in
the assembly of long fibrils that often leads to cell
death.
Catalysis: Many proteins are specialized to
catalyze, or speed up, chemical reactions. A
protein that functions as a catalyst is called an
enzyme.
Defense: Proteins called antibodies attack and
destroy viruses and bacteria that cause disease.
Movement: Motor proteins and contractile
proteins are responsible for moving the cell
itself, or for moving large molecules and other
types of cargo inside the cell.
Signaling: Proteins are involved in carrying and
receiving signals from cell to cell inside the body.
Many of them reside on the cell’s membrane to
interact with neighboring cells.
Structure: Structural proteins make up body
components such as fingernails and hair, and form
the internal “skeleton” of individual cells. Structural
proteins keep red blood cells flexible and in their
normal disc-like shape.
Transport: Proteins allow particular molecules to
enter and exit cells or carry them throughout the
body.
• Part of the reason enzymes are such effective catalysts
is that they hold substrates in a precise orientation so
they can react.
• The initial hypothesis for how enzymes work was
proposed by Emil Fischer in 1894.
• According to Fischer’s “lock-and-key” model, enzymes
are analogous to a lock and the keys are substrates that
fit into the lock and then react.
•The location where substrates bind and react became
known as the enzyme’s active site. The active site is
where catalysis actually occurs.
