Subjects

BIOLOGY

Chandrashekhar Singh

MACROMOLECULES

Proteins
Introduction to amino
acids

Peptide bond formation

Introduction to proteins
and amino acids
Overview of protein
structure
Tertiary structure of
proteins
Orders of protein
structure

BIOLOGY | MACROMOLECULES | PROTEINS

Orders of proteinstructure
Orders of protein structure: primary, secondary, tertiary,
and quaternary. Alpha helix and beta pleated sheet.
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Introduction
Have you ever wondered why egg whites go
from clear to opaque when you fry an egg? If so,
this section is for you!
Egg whites contain large amounts of proteins
called albumins, and the albumins normally have
a specic 3D shape, thanks to bonds formed
between dierent amino acids in the protein.
Heating causes these bonds to break and
exposes hydrophobic (water-hating) amino acids
usually kept on the inside of the protein1,2 . The
hydrophobic amino acids, trying to get away
from the water surrounding them in the egg
white, will stick to one another, forming a protein
network that gives the yolk structure and makes
it white and opaque. Ta-da! Thank you, protein
denaturation, for another delicious breakfast.
As we mentioned in the last article on proteins
and amino acids, the shape of a protein is very
important to its function. To understand how a
protein gets its nal shape or conformation, we

need to understand the four levels of protein

structure: primary, secondary, tertiary, and
quaternary.

Primary structure
The simplest level of protein structure, primary
structure, is simply the sequence of amino acids
in a polypeptide chain. For example, the
hormone insulin has two polypeptide chains, A
and B, shown in diagram below. (The insulin
molecule shown here is cow insulin, although its
structure is similar to that of human insulin.) Each
chain has its own set of amino acids, assembled
in a particular order. For instance, the sequence
of the A chain starts with glycine at the Nterminus and ends with asparagine at the Cterminus, and is dierent from the sequence of
the B chain. [What's up with those S-S bonds?]

image credit: OpenStax Biology.

The sequence of a protein is determined by the

DNA of the gene that encodes the protein (or
that encodes a portion of the protein, for multi-

subunit proteins). A change in the gene's DNA

sequence may lead to a change in the amino
acid sequence of the protein. Even changing just
one amino acid in a proteins sequence can
aect the proteins overall structure and function.
For instance, a single amino acid change is
associated with sickle cell anemia, an inherited
disease that aects red blood cells. In sickle cell
anemia, one of the polypeptide chains that make
up hemoglobin, the protein that carries oxygen
in the blood, has a slight sequence change. The
glutamate that is normally the seventh amino
acid of the hemoglobin chain (one of two types
of protein chains that make up hemoglobin) is
replaced by a valine. This substitution is shown
for a fragment of the chain in the diagram
below.

Image modied from OpenStax Biology.

What is most remarkable to consider is that a

hemoglobin molecule is made up of two chains
and two chains, each consisting of about 150
amino acids, for a total of about 600 amino acids

in the whole protein. The dierence between a

normal hemoglobin molecule and a sickle cell
molecule is just 2 amino acids out of the
approximately 600.
A person whose body makes only sickle cell
hemoglobin will suer symptoms of sickle cell
anemia. These occur because the glutamate-tovaline amino acid change makes the hemoglobin
molecules assemble into long bers. The bers
distort disc-shaped red blood cells into crescent
shapes. Examples of sickled cells can be seen
mixed with normal, disc-like cells in the blood
sample below.

Image credit: OpenStax Biology modication of work by Ed Uthman;

scale-bar data from Matt Russell.

The sickled cells get stuck as they try to pass

through blood vessels. The stuck cells impair
blood ow and can cause serious health
problems for people with sickle cell anemia,
including breathlessness, dizziness, headaches,
and abdominal pain.

Secondary structure
The next level of protein structure, secondary
structure, refers to local folded structures that
form within a polypeptide due to interactions
between atoms of the backbone. (The backbone
just refers to the polypeptide chain apart from
the R groups so all we mean here is that
secondary structure does not involve R group
atoms.) The most common types of secondary
structures are the helix and the pleated
sheet. Both structures are held in shape by
hydrogen bonds, which form between the
carbonyl O of one amino acid and the amino H
of another.

Image credit: OpenStax Biology.

In an helix, the carbonyl (C=O) of one amino

acid is hydrogen bonded to the amino H (N-H) of
an amino acid that is four down the chain. (E.g.,
the carbonyl of amino acid 1 would form a

hydrogen bond to the N-H of amino acid 5.) This

pattern of bonding pulls the polypeptide chain
into a helical structure that resembles a curled
ribbon, with each turn of the helix containing 3.6
amino acids. The R groups of the amino acids
stick outward from the helix, where they are
free to interact3 .
In a pleated sheet, two or more segments of a
polypeptide chain line up next to each other,
forming a sheet-like structure held together by
hydrogen bonds. The hydrogen bonds form
between carbonyl and amino groups of
backbone, while the R groups extend above and
below the plane of the sheet3 . The strands of a
pleated sheet may be parallel, pointing in the
same direction (meaning that their N- and Ctermini match up), or antiparallel, pointing in
opposite directions (meaning that the N-terminus
of one strand is positioned next to the Cterminus of the other).
Certain amino acids are more or less likely to be
found in -helices or pleated sheets. For
instance, the amino acid proline is sometimes
called a helix breaker because its unusual R
group (which bonds to the amino group to form a
ring) creates a bend in the chain and is not
compatible with helix formation4 . Proline is
typically found in bends, unstructured regions
between secondary structures. Similarly, amino
acids such as tryptophan, tyrosine, and
phenylalanine, which have large ring structures
in their R groups, are often found in pleated

sheets, perhaps because the pleated sheet

structure provides plenty of space for the side
chains4 .
Many proteins contain both helices and
pleated sheets, though some contain just one
type of secondary structure (or do not form
either type).

Tertiary structure
The overall three-dimensional structure of a
polypeptide is called its tertiary structure. The
tertiary structure is primarily due to interactions
between the R groups of the amino acids that
make up the protein.
R group interactions that contribute to tertiary
structure include hydrogen bonding, ionic
bonding, dipole-dipole interactions, and London
dispersion forces basically, the whole gamut of
non-covalent bonds. For example, R groups with
like charges repel one another, while those with
opposite charges can form an ionic bond.
Similarly, polar R groups can form hydrogen
bonds and other dipole-dipole interactions. Also
important to tertiary structure are hydrophobic
interactions, in which amino acids with nonpolar,
hydrophobic R groups cluster together on the
inside of the protein, leaving hydrophilic amino
acids on the outside to interact with surrounding
water molecules.

Finally, theres one special type of covalent bond

that can contribute to tertiary structure: the
disulde bond. Disulde bonds, covalent
linkages between the sulfur-containing side
chains of cysteines, are much stronger than the
other types of bonds that contribute to tertiary
structure. They act like molecular "safety pins,"
keeping parts of the polypeptide rmly attached
to one another.

Image modied from OpenStax Biology.

Quaternary structure
Many proteins are made up of a single
polypeptide chain and have only three levels of
structure (the ones weve just discussed).
However, some proteins are made up of multiple
polypeptide chains, also known as subunits.
When these subunits come together, they give
the protein its quaternary structure.

Weve already encountered one example of a

protein with quaternary structure: hemoglobin.
As mentioned earlier, hemoglobin carries oxygen
in the blood and is made up of four subunits, two
each of the and types. Another example is
DNA polymerase, an enzyme that synthesizes
new strands of DNA and is composed of ten
subunits5 .
In general, the same types of interactions that
contribute to tertiary structure (mostly weak
interactions, such as hydrogen bonding and
London dispersion forces) also hold the subunits
together to give quaternary structure.

Image modied from OpenStax Biology's modication of work by the

National Human Genome Research Institute.

Denaturation and protein

folding
Each protein has its own unique shape. If the
temperature or pH of a protein's environment is
changed, or if it is exposed to chemicals, these
interactions may be disrupted, causing the
protein to lose its three-dimensional structure
and turn back into an unstructured string of
amino acids. When a protein loses its higherorder structure, but not its primary sequence, it is
said to be denatured. Denatured proteins are
usually non-functional.
For some proteins, denaturation can be
reversed. Since the primary structure of the
polypeptide is still intact (the amino acids havent
split up), it may be able to re-fold into its
functional form if it's returned to its normal
environment. Other times, however, denaturation
is permanent. One example of irreversible
protein denaturation is when an egg is fried. The
albumin protein in the liquid egg white becomes
opaque and solid as it is denatured by the heat
of the stove, and will not return to its original,
raw-egg state even when cooled down.
Researchers have found that some proteins can
re-fold after denaturation even when they are
alone in a test tube. Since these proteins can go

from unstructured to folded all by themselves,

their amino acid sequences must contain all the
information needed for folding. However, not all
proteins are able to pull o this trick, and how
proteins normally fold in a cell appears to be
more complicated. Many proteins dont fold by
themselves, but instead get assistance from
chaperone proteins (chaperonins).
[Hide references]

Attribution:
This article is a modied derivative of Proteins,
by OpenStax College, Biology (CC BY 3.0).
Download the original article for free at
http://cnx.org/contents/185cbf87-c72e-48f5b51e-f14f21b5eabd@9.85:13/Biology.
The modied article is licensed under a CC BYNC-SA 4.0 license.

Works cited:
1. Watt, Jeremy. (2010, February 1). The
denatured egg white. In Moment of
science. Retrieved from

http://indianapublicmedia.org/amomentofscience/d
2. Egg white. (2015, July 20). Retrieved July
25, 2015 from Wikipedia:
https://en.wikipedia.org/wiki/Egg_white.

3. Berg, J. M., Tymoczko, J. L., and Stryer, L.

(2002). Secondary structure: Polypeptide
chains can fold into regular structures such
as the alpha helix, the beta sheet, and turns
and loops. In Biochemistry (5th ed., section
3.3). New York, NY: W. H. Freeman.
Retrieved from
http://www.ncbi.nlm.nih.gov/books/NBK22580/

4. Protein secondary structure. (2015, June

16). Retrieved July 25, 2015 from Wikipedia:
https://en.wikipedia.org/wiki/Protein_secondary_st
5. Marians, K. J., Hiasa, H., Kim, D. R., and
McHenry, C.S. (1998). Role of the Core DNA
Polymerase III Subunits at the Replication
Fork. J. Biol. Chem., 273, 2452-2457.
http://doi.org/10.1074/jbc.273.4.2452.

Additional references:
Berg, J. M., Tymoczko, J. L., and Stryer, L. (2002).
Secondary structure: Polypeptide chains can
fold into regular structures such as the alpha
helix, the beta sheet, and turns and loops. In

Biochemistry (5th ed., section 3.3). New York,

NY: W. H. Freeman. Retrieved from
http://www.ncbi.nlm.nih.gov/books/NBK22580/.
Berg, J. M., Tymoczko, J. L., and Stryer, L. (2002).
Tertiary structure: Water-soluble proteins fold
Into compact structures with nonpolar cores. In

Biochemistry (5th ed., section 3.4). New York,

NY: W. H. Freeman. Retrieved from

http://www.ncbi.nlm.nih.gov/books/NBK22375/.
Egg white. (2015, July 20). Retrieved July 25,
2015 from Wikipedia:
https://en.wikipedia.org/wiki/Egg_white.
Keratin. (2015, 24 July). Retrieved July 25, 2015
from Wikipedia:
https://en.wikipedia.org/wiki/Keratin.
Protein secondary structure. (2015, June 16).

Retrieved July 25, 2015 from Wikipedia:

https://en.wikipedia.org/wiki/Protein_secondary_structu
Protein quaternary structure. (2015, July 21).
Retrieved July 25, 2015 from Wikipedia:

https://en.wikipedia.org/wiki/Protein_quaternary_structu
Raven, P. H., Johnson, G. B., Mason, K. A., Losos,
J. B., and Singer, S. R. (2014). Proteins:
Molecules with diverse structures and functions.
In Biology (10th ed., AP ed., pp. 44-53). New
York, NY: McGraw-Hill.
Reece, J. B., Urry, L. A., Cain, M. L., Wasserman,
S. A., Minorsky, P. V., and Jackson, R. B. (2011).
Proteins include a diversity of structures,
resulting in a wide range of functions. In

Campbell biology (10th ed., pp. 75-84). San

Francisco, CA: Pearson.
Watt, Jeremy. (2010, February 1). The denatured
egg white. In Moment of science. Retrieved from

http://indianapublicmedia.org/amomentofscience/dena

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Top Recent

When we digest meals rich in protein, are we denaturing

the proteins and "re-naturing" them through the help of
chaperonins, or breaking it down to it's base amino acids
and re-creating proteins using those?
20 votes

Comment Flag
about a year ago by

Kam

Oftentimes, we are breaking them down to their

amino acid bases and creating new proteins. This is
because many of the proteins that are found in the
human body are not directly consumed through
food, rather we need certain proteins in the food so
we can use their amino acids to build the proteins
that we need. The human body does not produce all
23 amino acids, so we need to get them from our
food, by eating proteins that contain those amino
acids. :)
13 votes

4 comments Flag
about a year ago by

Darmon

Show all 3 answers Answer this question

What is the N-terminus and C-terminus mentioned in

primary structure?
6 votes

1 comment Flag
about a year ago by

sewerrat616

The N-terminus refers to the amino end of the amino

acid with the nitrogen and hydrogens, and the C-

terminus refers to the carboxyl group.

9 votes

Comment Flag
about a year ago by

Vaishnavi

Show all 4 answers Answer this question

In the Primary Structure section when they're talking

about Hemoglobin and sickle cell:
"What is most remarkable to consider is that a
hemoglobin molecule is made up of two chains and two
chains, each consisting of about 150 amino acids, for a
total of about 600 amino acids in the whole protein."
What do they mean by two Alpha chains and two Beta
chains? Do they mean two polypeptides in an Alpha helix
shape and two polypeptides in a Beta pleated sheet
shape? Or are they just calling two of (more)
5 votes

Comment Flag
about a year ago by

Sean Collin

"Do they mean two polypeptides in an Alpha helix

shape and two polypeptides in a Beta pleated sheet
shape?"
- Yes, this is what they mean.
"Or are they just calling two of the polypeptides
"alpha" because they're both identical and the other
two "beta" because they're also identical."
- And yes, both alphas are similar and both betas are
similar.
Hope this helps!
3 votes

Comment Flag
about a year ago by

Nick Whitbeck

Show all 2 answers Answer this question

In the last paragraph they begin to talk about Proteins

"folding" but they don't explain what this means.

2 votes

Comment Flag
about a year ago by

Sean Collin

Proteins can fold into various structures/sizes

(secondary, tertiary, quanternary) for various
biological tasks. Think of it literally as proteins
folding into smaller, more condensed forms.
2 votes

Comment Flag
about a year ago by

Nick Whitbeck

Examples of 4 levels of protiens .

1 vote

Comment Flag
12 months ago by

Abhishek singh

I think you mean "examples of the four levels of

structure in a protein," and if that is the case you can
look at the very last image in the article, it provides
examples of the primary, secondary, tertiary, and
quaternary structures covered in the article.
2 votes

Comment Flag
8 months ago by

Alex Randomkat

I was wondering about the secondary structure- what

causes them to form or take shape?
1 vote

Comment Flag
2 months ago by

Sannia Hagag

Hydrogen bonding (carbonyl O of one amino acid

and the amino H of another)
2 votes

1 comment Flag
15 days ago by

Avanti Shah

so is the B-pleated sheet parallel or antiparallel?

1 vote

Comment Flag

5 months ago by

Bella

It can be both. If the two chains of amino acid are in

the same direction, they form 'parallel beta-pleated
sheet''; if they are in the opposite direction, they
form 'anti-parallel beta-pleated sheet'.
1 vote

2 comments Flag
5 months ago by

Caresse Zhu

In the subsection on Tertiary Structure, it is mentioned

that Disulde bonds are much stronger than the other
types of bonds contributing to Tertiary Structure of
proteins. What is it about these S-S linkages that makes
them so strong? And in relation to that: What determines
whether or not an ionic/covalent bond is strong or weak?
1 vote

Comment Flag

3 months ago by

Jack Lance

The S-S linkages are actual covalent bonds which

are inherently much stronger than the intermolecular bonds.
1 vote

Comment Flag
3 months ago by

John Morgenthaler

It goes in depth about the structures, but lacks in

explaining function. Besides holding other primary
structure proteins, what does a tertiary and quaternary
structure even do?

1 vote

Comment Flag

2 months ago by

juvaldez50

The function of tertiary and quaternary structure

varies depending on type of protein, but in enzymes,
the specic shape and conguration of the protein
allows the formation of active sites. For example,
catalase, an enzyme that breaks hydrogen peroxide
into hydrogen and oxygen gas, has its proteins and
amino acids congured in a certain way to create an
area where the charges are so strong that
spontaneous reaction occurs, by lowering the
energy needed to break intermolecular bonds.
1 vote

Comment Flag
2 months ago by

Katherine Lu

what are the examples of all protein layers?

1 vote

Comment Flag
2 months ago by

Hinza Shahid

Secondary: Wool, hair, silk

Tertiary: Enzymes (their 3D conformation allows the
formation of active sites)
Quaternary: Haemoglobin (haem- prosthetic group)
1 vote

Comment Flag
15 days ago by

Show more comments

Tertiary structure of proteins

Avanti Shah