Amino Acids and Peptides

The word protein that I propose to you . . . I

would wish to derive from proteios, because it
appears to be the primitive or principal substance
of animal nutrition that plants prepare for the
herbivores, and which the latter then furnish to
the carnivores.
—J. J. Berzelius, letter to G. J. Mulder, 1838
Proteins are the most abundant biological
macromolecules, occurring in all cells and all parts
of cells. Proteins also occur in great variety;
thousands of different kinds may be found in a
single cell. Proteins are the molecular instruments
through which genetic information is expressed.
All proteins, whether from the most ancient lines
of bacteria or from the most complex forms of life,
are constructed from the same ubiquitous set of
20 amino acids, covalently linked in characteristic
linear sequences.
Proteins are found in a wide range of sizes, from
relatively small peptides with just a few amino acid
residues to huge polymers with molecular weights in the
millions. cells can produce proteins with strikingly
different properties and activities by joining the same 20
amino acids in many different combinations and
sequences.
From these building blocks different organisms can
make such widely diverse products as enzymes,
hormones, antibodies, transporters, muscle
fibers, the lens protein of the eye, feathers, spider
webs, rhinoceros horn, milk proteins, antibiotics,
mushroom poisons, and myriad other substances
having distinct biological activities
 Proteins are polymers of amino acids, with each amino
acid residue joined to its neighbor by a specific type of
covalent bond. Twenty different amino acids are
commonly found in proteins. The first to be discovered
was asparagine, in 1806. The last of the 20 to be found,
threonine, was not identified until 1938. All the amino
acids have trivial or common names, in some cases
derived from the source from which they were first
isolated. Asparagine was first found in asparagus, and
glutamate in wheat gluten; tyrosine was first isolated
from cheese (its name is derived from the Greek tyros,
“cheese”); and glycine (Greek glykos, “sweet”) was so
named because of its sweet taste.
All 20 of the common amino acids are α-amino acids. They
have a carboxyl group and an amino group bonded to the
same carbon atom (the carbon) (Fig. 3–2). They differ from
each other in their side chains, or R groups, which vary in
structure, size, and electric charge, and which influence the
solubility of the amino acids in water. In addition to these 20
amino acids there are many less common ones. Some are
residues modified after a protein has been synthesized; others
are amino acids present in living organisms but not as
constituents of proteins. The common amino acids of proteins
have been assigned three letter abbreviations and one-letter
symbols (Table 3–1), which are used as shorthand to indicate the
composition and sequence of amino acids polymerized in
proteins.
 A carbon atom with four different substituents is said to be
asymmetric, and asymmetric carbons are called chiral centers
(Greek chiros, “hand”; some stereoisomers are related
structurally as the right hand is to the left).
A molecule with only one chiral carbon can have two
stereoisomers; when two or more (n) chiral carbons are present,
there can be 2n stereoisomers. Stereoisomers that are mirror
images of each other are called enantiomers (Fig. 1–19). Pairs of
stereoisomers that are not mirror images of each other are called
diastereomers (Fig. 1–20).
Two conventions are used to identify the carbons in an amino acid—a practice that
can be confusing. The additional carbons in an R group are commonly designated β ,
γ, δ , ε , and so forth, proceeding out from the carbon. For most other organic
molecules, carbon atoms are simply numbered from one end, giving highest priority
(C-1) to the carbon with the substituent containing the atom of highest atomic
number.
Nearly all biological compounds with a chiral center occur
naturally in only one stereoisomeric form, either D or L. The amino acid
residues in protein molecules are exclusively L stereoisomers. D-Amino acid
residues have been found in only a few, generally small peptides, including
some peptides of bacterial cell walls and certain peptide antibiotics. It is
remarkable that virtually all amino acid residues in proteins are L
stereoisomers.
When chiral compounds are formed by ordinary chemical reactions,
the result is a racemic mixture of D and L isomers, which are difficult for a
chemist to distinguish and separate. But to a living system, D and L isomers
are as different as the right hand and the left. The formation of stable,
repeating substructures in proteins generally requires that their constituent
amino acids be of one stereochemical series. Cells are able to specifically
synthesize the L isomers of amino acids because the active sites of enzymes
are asymmetric, causing the reactions they catalyze to be stereospecific
Amino Acids Can Be Classified by R Group

Knowledge of the chemical properties of the common amino acids is central to an

understanding of biochemistry. The topic can be simplified by grouping the amino
acids into five main classes based on the properties of their R groups (Table 3–1), in
particular, their polarity, or tendency to interact with water at biological pH (near
pH 7.0). The polarity of the R groups varies widely, from nonpolar and hydrophobic
(water-insoluble) to highly polar and hydrophilic (water-soluble).
The structures of the 20 common amino acids are shown in Figure 3–5, and some of
their properties are listed in Table 3–1.
Nonpolar, Aliphatic R Groups The R groups in this class of amino acids are
nonpolar and hydrophobic. The side chains of alanine, valine, leucine, and
isoleucine tend to cluster together within proteins, stabilizing protein structure
by means of hydrophobic interactions. Glycine has the simplest structure.
Although it is most easily grouped with the nonpolar amino acids, its very small
side chain makes no real contribution to hydrophobic interactions. Methionine,
one of the two sulfur-containing amino acids, has a nonpolar thioether group in
its side chain. Proline has an aliphatic side chain with a distinctive cyclic structure.
The secondary amino (imino) group of proline residues is held in a rigid
conformation that reduces the structural flexibility of polypeptide regions
containing proline
Aromatic R Groups Phenylalanine, tyrosine, and tryptophan, with their
aromatic side chains, are relatively nonpolar (hydrophobic). All can
participate in hydrophobic interactions. The hydroxyl group of tyrosine
can form hydrogen bonds, and it is an important functional group in some
enzymes. Tyrosine and tryptophan are significantly more polar than
phenylalanine, because Tryptophan and tyrosine, and to a much lesser extent
phenylalanine, absorb ultraviolet light (Fig. 3–6;. This accounts for the
characteristic strong absorbance of light by most proteins at a wavelength
of 280 nm, a property exploited by researchers in the characterization of
proteins.
Polar, Uncharged R Groups The R groups of these
amino acids are more soluble in water, or more hydrophilic, than those of the
nonpolar amino acids, because they contain functional groups that form
hydrogen bonds with water. This class of amino acids includes serine, threonine,
cysteine, asparagine, and glutamine. The polarity of serine and threonine
is contributed by their hydroxyl groups; that of cysteine by its sulfhydryl group,
which is a weak acid and can make weak hydrogen bonds with oxygen or nitrogen;
and that of asparagine and glutamine by their amide groups.
Asparagine and glutamine are the amides of two other amino acids also found in
proteins, aspartate and glutamate, respectively, to which asparagine and
glutamine are easily hydrolyzed by acid or base. Cysteine is readily oxidized to form
a covalently linked dimeric amino acid called cystine, in which two cysteine
molecules or residues are joined by a disulfide bond (Fig. 3–7). The disulfide-linked
residues are strongly hydrophobic (nonpolar). Disulfide bonds play a special role in
the structures of many proteins by forming covalent links between parts of a
polypeptide molecule or between two different polypeptide chains.
(Fig. 3–7).
Positively Charged (Basic) R Groups The most hydrophilic R groups are those
that are either positively or negatively charged. The amino acids in which the R
groups have significant positive charge at pH 7.0 are lysine, which has a second
primary amino group at the position on its aliphatic chain; arginine, which has
a positively charged guanidinium group; and histidine, which has an aromatic
imidazole group. As the only common amino acid having an ionizable side chain
with pKa near neutrality, histidine may be positively charged (protonated form)
or uncharged at pH 7.0. His residues facilitate many enzyme-catalyzed reactions
by serving as proton donors/acceptors.

Negatively Charged (Acidic) R Groups The two

amino acids having R groups with a net negative charge at pH 7.0 are aspartate
and glutamate, each of which has a second carboxyl group.
Amino acids to calm down and Pep up

Some people insist that supplements of Tyrosine give them a morning

lift and that tryptophan helps them sleep at night .Milk proteins have
high levels of tryptophan ; a glass of warm milk before bed is widely
believed to be an aid in inducing sleep. Cheese and red wines contain
high amounts of tyramine , which mimics epinephrine ; for many people
a cheese omelet in the morning is a favorite way to a start the day.
Uncommon Amino Acids Also Have Important Functions
In addition to the 20 common amino acids, proteins may contain residues created by
modification of common residues already incorporated into a polypeptide
(Fig. 3–8a). Among these uncommon amino acids are 4-hydroxyproline, a derivative of
proline, and 5-hydroxylysine, derived from lysine. The former is found in plant cell wall
proteins, and both are found in collagen, a fibrous protein of connective tissues.
6-N-Methyllysine is a constituent of myosin, a contractile protein of muscle. Another
important uncommon amino acid is γ-carboxyglutamate, found in the blood clotting
protein prothrombin and in certain other proteins that bind Ca2 as part of their
biological function. More complex, a derivative of four Lys residues, which is found in
the fibrous proteis desmosine in elastin. Selenocysteine is a special case. This rare
amino acid residue is introduced during protein synthesis rather than created through a
postsynthetic modification. It contains selenium rather than the sulfur of cysteine.
Actually derived from serine, selenocysteine is a constituent of just a few known
proteins
Some amino acid residues in a protein may be modified transiently to alter the
protein’s function. The addition of phosphoryl, methyl, acetyl, adenylyl, ADPribosyl,
or other groups to particular amino acid residues can increase or decrease a
protein’s activity. Some 300 additional amino acids have been found in cells. They
have a variety of functions but are not all constituents of proteins. Ornithine and
citrulline
FIGURE 3–8 Uncommon amino acids. (a) Some uncommon amino
acids found in proteins. All are derived from common amino acids.
Extra functional groups added by modification reactions are shown
in red. Desmosine is formed from four Lys residues (the four carbon
backbones are shaded in yellow). Note the use of either numbers or
Greek letters to identify the carbon atoms in these structures. (b)
Reversible amino acid modifications involved in regulation of
protein activity. Phosphorylation is the most common type of
regulatory modification.
(c) Ornithine and citrulline, which are not found in proteins, are
intermediates in the biosynthesis of arginine and in the urea cycle.
(b) Reversible amino acid modifications involved in regulation of protein
activity. Phosphorylation is the most common type of regulatory
modification.
(b) Reversible amino acid modifications involved in
regulation of protein activity. Phosphorylation is the most
common type of regulatory modification.
Uncommon amino acids results from posttranslational modification,
Found only in few connective tissue proteins such as collagen.
Thyroxine hormone: is a modification of tyrosine that produced
in thyroid gland.
3.3 Amino acids can act as both acids and bases
• In free amino acids at neutral pH, the carboxylate
group is negatively charged and the amino group is
positively charged.
• Amino acids without charged groups on their side
chains exist in neutral solution as zwitterions, with no
net charge.
• Titration curves of amino acids indicate the pH ranges
in which titratable groups gain or lose a proton.
• Side chains of amino acids can also contribute
titratable groups; the charge (if any) on the side chain
must be taken into consideration in determining the
net charge on the amino acid.
Amino acid Charge dependence on pH:
I. Zwitterions : no net charge on a.a
II. Isoelectric pH (pI): the pH at which the
molecule/a.a has no net charge
III. Electrophoresis: common method of
separating molecule in an electrical field
The ionic forms of the amino acids, shown without consideration of any ionizations
on the side chain. The cationic form is the low-pH form, and the titration of the
cationic species with base yields the zwitterions and finally the anionic form.
The titration curve of alanine
The ionization of histidine (an amino acid with a titratable side chain).
The titration curve of histidine
Peptides are formed by linking the carboxyl group of one
amino acid to the amino group of another amino acid in a
covalent (amide) bond.
Proteins consist of polypeptide chains; the number of
amino acids in a protein is usually 100 or more.
The peptide group is planar as a result of resonance
stabilization, this stereochemical constraint plays an
important role in determining the three-dimensional
structures of peptides and proteins.
Three amino acids can be joined by two peptide bonds to
form a tripeptide; similarly, four amino acids can be linked to
form tetrapeptides, five to form pentapeptides, and so forth.
When a few amino acids are joined in this fashion, the
structure is called an oligopeptide. When many amino acids
are joined, the product is called a polypeptide. Proteins may
have thousands of amino acid residues. Although the terms
“protein” and “polypeptide” are sometimes used
interchangeably, molecules referred to as polypeptides
generally have molecular weights below 10,000, and those
called proteins have higher molecular weights.
The resonance structures of the peptide bond lead to a planar group.
(a) Resonance structures of the peptide group.
(b) The planar peptide group.
A small peptide showing the direction of the
peptide chain (N-terminal to C-terminal)
SOME IMPORTANT
PHYSIOLOGICAL
PEPTIDES
DIPEPTIDES
Fig. 3-11, p.72
Is it Carnosine?
TRIPEPTIDES

Fig. 3-12, p.74

Fig. 3-12a, p.74
Fig. 3-12b, p.74
Fig. 3-12c, p.74
 Enkephalin- It is a pentapeptides

• Two kinds of Enkaphalins:

1-Leucine Enkaphalin
Tyr Gly Gly Phe Leu
2- Methionine Enkaphalin
Tyr Gly Gly Phe Met
Both exist in the brain , and they are considered as
Analgesics ( pain relievers )

The aromatic side chains of both Tyrosine and Phenyalanine play

an important role in the physiological activities
Fig. 3-13a, p.75
Fig. 3-13b, p.75
A Dipeptide
A sweetener
(Aspartame )
(NaturaSweet)

p.73b
p.73a
3.5 Small Peptides with Physiological Activity :Summary
• Small peptides, containing two to several dozen amino
acid residues, can have marked physiological effects in
organisms.
• Carnosine is naturally occurring dipeptides (β-alanine
and Histidine) in muscle tissue.
• Oxytocin has an isoleucine
at position 3 and a leucine
at position 8; it stimulates
smooth muscle contraction
in the uterus during labor
and in the mammary glands
during lactation.

• Vasopressin has a
phenylalanine at position 3
and an arginine at position
8; it stimulates reabsorption
of water by the kidneys,
thus raising blood pressure.
• Glutathione is a
commonly tripeptide
that acts as a scavengers
of oxidizing agents.

• Enkephalins are
pentapeptides (Y-G-G-F-
L, leucine enkephalin,
and Y-G-G-F-M,
methionine enkephalin),
which are naturally
occurring analgesics
(Pain relievers).
 Protein Classification
• Simple – composed only of amino acid residues

• Conjugated – contain prosthetic groups

(metal ions, co-factors, lipids, carbohydrates)
Example: Hemoglobin – Heme
4 Levels of Protein Structure
3.4 The Structure of Proteins: Primary
Structure What is it that makes one protein an enzyme, another
a hormone, another a structural protein, and still another an
antibody? How do they differ chemically?
The most obvious distinctions are structural, and to protein
structure we now turn. Four levels of protein structure are commonly
defined (Fig. 3–23). A description of all covalent bonds (mainly
peptide bonds and disulfide bonds) linking amino acid residues in a
polypeptide chain is its primary structure. The most important
element of primary structure is the sequence of amino acid residues.
Secondary structure refers to particularly stable arrangements of
amino acid residues giving rise to recurring structural patterns.
Tertiary structure describes all aspects of the three-dimensional
folding of a polypeptide. When a protein has two or more polypeptide
subunits, their arrangement in space is referred to as quaternary
structure.
Levels of Protein Structure
Structurally ,proteins can be organized into
four levels :
1-Primary .
2-Secondary.
3-Tertiary .
4-Quaternary.
The differences in primary structure can be especially informative. Each protein has
a distinctive number and sequence of amino acid residues. The primary structure of
a protein determines how it folds up into its unique three-dimensional structure,
and this in turn determines the function of the protein.

Each type of protein has a unique three-dimensional structure and this structure
confers a unique function.
Each type of protein also has a unique amino acid sequence.

Intuition suggests that the amino acid sequence must play a fundamental role in
determining the three-dimensional structure of the protein, and ultimately its
function,

Is that correct ????????????????????????????

What do you think?

1o Structure Determines 2o, 3o, 4o Structure

• Sickle Cell Anemia – single amino acid

change in hemoglobin related to this
disease
Sickle cell anemia (SCA ) or
Sickle cell disease (SCD )

• Sickle-cell anaemia is caused by a mutation in

the globin chain of haemoglobin, causing the
hydrophilic amino acid glutamic acid to be
replaced with the hydrophobic amino acid
valine at the sixth position.
• Osteoarthritis – single amino acid change
• ( replacement of Glycine by another amino acid ) in
collagen protein causes joint damage
First, as we have already noted, proteins with different functions always have different
amino acid sequences. Second, thousands of human genetic diseases have been traced
to the production of defective proteins. The defect can range from a single change in the
amino acid sequence as in sickle cell anemia to deletion of a larger portion of the
polypeptide chain (as in most cases of Duchenne muscular dystrophy: a large deletion in
the gene encoding the protein dystrophin leads to production of a shortened,
inactive protein). Thus we know that if the primary structure is altered, the function of
the protein may also be changed. Finally, on comparing functionally similar proteins
from different species, we find that these proteins often have similar amino acid
sequences. An extreme case is ubiquitin, a 76-residue protein involved in regulating the
degradation of other proteins. The amino acid sequence of ubiquitin is identical in
species as disparate as fruit flies and humans.

Is the amino acid sequence absolutely fixed, or invariant, for a particular

protein? No; some flexibility is possible. An estimated 20% to 30% of the proteins in
humans are polymorphic, having amino acid sequence variants in the human population
Furthermore, proteins that carry out a broadly similar function in distantly related
species can differ greatly in overall size and amino acid sequence.

The Amino Acid Sequences of Millions of Proteins Have Been

Determined
Two major discoveries in 1953 were of crucial importance in
the history of biochemistry. In that year, James D. Watson and
Francis Crick deduced the double-helical structure of DNA and
proposed a structural basis for its precise replication . Their
proposal illuminated the molecular reality behind the idea of a
gene. In the same year, Frederick Sanger worked out the
sequence of amino acid residues in the polypeptide chains of
the hormone insulin (Fig. 3–24). a decade after these
discoveries, the genetic code relating the nucleotide sequence
of DNA to the amino acid sequence of protein molecules was
elucidated.
Short Polypeptides Are Sequenced with Automated Procedures
Various procedures are used to analyze protein primary structure. To start,
biochemists have several strategies for labeling and identifying the amino-terminal
amino acid residue (Fig. 3–25a). Sanger developed the reagent 1-fluoro-2,4-
dinitrobenzene (FDNB) for this purpose; other available reagents are dansyl
chloride and dabsyl chloride, which yield derivatives that are more easily
detectable than the dinitrophenyl derivatives. After the amino-terminal residue is
labeled with one of these reagents, the polypeptide is hydrolyzed (in 6 M HCl) to
its constituent amino acids and the labeled amino acid is identified. Because the
hydrolysis stage destroys the polypeptide, this procedure cannot be used to
sequence a polypeptide beyond its amino-terminal residue. However, it can help
determine the number of chemically distinct polypeptides in a protein, provided
each has a different amino-terminal residue. For example, two residues—Phe and
Gly—would be labeled if insulin (Fig. 3–24) were subjected to this procedure.
To sequence an entire polypeptide, a chemical method devised by
Pehr Edman is usually employed. The Edman degradation
procedure labels and removes only the amino-terminal residue
from a peptide, leaving all other peptide bonds intact (Fig. 3–25b).
The peptide is reacted with phenylisothiocyanate under mildly
alkaline conditions, which converts the aminoterminal amino acid
to a phenylthiocarbamoyl (PTC) adduct. The peptide bond next to
the PTC adduct is then cleaved in a step carried out in anhydrous
trifluoroacetic acid, with removal of the amino-terminal amino acid
as an anilinothiazolinone derivative. The derivatized amino acid is
extracted with organic solvents, converted to the more stable
phenylthiohydantoin derivative by treatment with aqueous acid,
and then identified. The use of sequential reactions carried out
under first basic and then acidic conditions provides a means of
controlling the entire process.
After removal and identification of the aminoterminal
residue, the new amino-terminal residue so exposed can
be labeled, removed, and identified through the same
series of reactions. This procedure is repeated until the
entire sequence is determined. The Edman degradation
is carried out in a machine, called a sequenator, that
mixes reagents in the proper proportions, separates the
products, identifies them, and records the results.
 Primary sequence reveals important clues
about a protein

• Evolution conserves amino acids that are important to protein structure and
function across species. Sequence comparison of multiple “homologs” of a
particular protein reveals highly conserved regions that are important for
function.

• Clusters of conserved residues are called “motifs” -- motifs carry out a

particular function or form a particular structure that is important for the
conserved protein.
Charged and polar R-groups tend
to map to protein surfaces
Non-polar R-groups tend to be buried in
the cores of proteins

Myoglobin
Blue = non-polar
R-group

Red = Heme
 Classes of 2 Structure
o

• Alpha- helix
• B-sheet
• Loops and turns
Secondary structure of proteins

1-Secondary structure is the hydrogen-bonded arrangement in

space of the backbone, the polypeptide chain.
2-Some of the most important backbone arrangements are the
α-helix, the β-sheet, and the β-turn.
3-They can be combined in a number of ways to produce
structural motifs that occur in many proteins.
4-Domain or super-secondary structure: independent folded
portion of protein.
Alpha-Helix
•Rise per residue: 1.5
Right handed
Angstroms
helix
•Rise per turn (pitch): 3.6
x 1.5A = 5.4 Angstroms
•Residues per turn: 3.6
•amino hydrogen H-bonds
with carbonyl oxygen
located 4 AA’s away forms
13 atom loop
Alpha-Helix

All H-bonds in the alpha-helix

are oriented in the same
direction giving the helix a dipole
with the N-terminus being
positive and the C-terminus
being negative
 Alpha-Helix
• Is a rodlike and involves one polypeptide
• It is stabilized by H-bonds parallel to the helix axis within the
backbone of single polypeptide chain.
• Proteins have varying amount of alpha-helix structures ( few
to 100%)
• Proline creates a bend in the backbone of alpha-helix. It can
not fit in the structure because :
• 1) Rotation around the bond N-alpha C is restricted
• 2) Proline’s alpha-amino group can not participate in
interachain hydrogen bonding
• Other amino acids (- or + charged) may cause the disruption
Alpha-Helix
•Side chain groups point
outwards from the helix
•AA’s with bulky side chains less
common in alpha-helix
•Glycine and proline destabilize
alpha-helix
α-helix
1- Coil of the helix is clockwise or right-handed
2- There are 3.6 amino acids per turn
3- Repeat distance is 5.4Å
4- Each peptide bond is trans and planar
5- C=O of each peptide bond is hydrogen
bonded to the N-H of the fourth amino acid
away
6- C=O----H-N hydrogen bonds are parallel to
helical axis
7- All R groups point outward from helix
Definition of the angles that
determine the conformation of
a polypeptide chain. The rigid
planar peptide groups (called
“playing cards” in the text) are
shaded. The angle of rotation
around the C-N bond is
designated  (phi), and the
angle of rotation around the

-C bond is designated ѱ

(psi). These two bonds are the
ones around which there is
freedom of rotation

Fig. 4-1, p.83

Fig. 4-2a, p.84
The three-dimensional
structure of two proteins
with substantial amounts
of -helix in their
structures. The helices are
represented by the
regularly coiled sections of
the ribbon diagram

Fig. 4-3a, p.85

The protein in helices are
represented by the regularly
coiled sections of the ribbon
diagram. Myohemerythrin is an
oxygen-carrying in invertebrates

Fig. 4-3b, p.85

4.2 Protein Secondary Structure
The term secondary structure refers to any chosen segment of a
polypeptide chain and describes the local spatial arrangement of
its main-chain atoms, without regard to the conformation of its
side chains or its relationship to other segments. A regular
secondary structure occurs when each dihedral angle, φ and ψ ,
remains the same or nearly the same throughout the segment.
There are a few types of secondary structure that are particularly
stable and occur widely in proteins. The most prominent are the α
helix and β conformations; another common type is the β turn.
Where a regular pattern is not found, the secondary structure is
sometimes referred to as undefined or as a random coil. This last
designation, however, does not properly describe the structure of
these segments. The path of the polypeptide backbone in almost
any protein is not random; rather, it is typically unchanging and
highly specific to the structure and function of that particular
protein. Our discussion here focuses on the regular, common
structures.
 The Helix Is a Common Protein Secondary Structure
The simplest arrangement the polypeptide chain can assume, given its rigid peptide
bonds (but free rotation around its other, single bonds), is a helical structure,
which Pauling and Corey called the α helix (Fig. 4–4). In this structure the polypeptide
backbone is tightly wound around an imaginary axis drawn longitudinally
through the middle of the helix, and the R groups of the amino acid residues protrude
outward from the helical backbone. The repeating unit is a single turn of the helix,
which extends about 5.4 A along the long axis, slightly greater than the periodicity
Astbury observed on x-ray analysis of hair keratin. The amino acid residues in the
prototypical helix have conformations with φ= - 57 and ψ=- 47, and each helical turn
includes 3.6 amino acid residues. The -helical segments in proteins often
deviate slightly from these dihedral angles, and even vary somewhat within a single
contiguous segment to produce subtle bends or kinks in the helical axis. In all
proteins, the helical twist of the helix is right-handed (Box 4–1). The helix proved to be
the predominant structure in -keratins. More generally, about one fourth
of all amino acid residues in proteins are found in helices, the exact fraction varying
greatly from one protein to another.
Why does the helix form more readily than many other possible conformations?
The answer is, in part, that an helix makes optimal use of internal hydrogen

bonds. The structure is stabilized by a hydrogen bond between the hydrogen atom attached
to the electronegative nitrogen atom of a peptide linkage and the electronegative
carbonyl oxygen atom of the fourth amino acid on the amino-terminal side of that peptide
bond (Fig. 4–4a). Within the helix, every peptide bond (except those close to each end of
the helix) participates in such hydrogen bonding. Each successive turn of the helix is held to
adjacent turns by three to four hydrogen bonds, conferring significant stability on the
overall structure. Further model-building experiments have shown that an α helix can form
in polypeptides consisting of either L- or D-amino acids. However, all residues must be
of one stereoisomeric series; a D-amino acid will disrupt a regular structure consisting of L-
amino acids, and vice versa. In principle, naturally occurring L-amino acids can form either
right- or left-handed helices, but extended left-handed helices are theoretically less stable
and have not been observed in proteins.
•The three-dimensional form of the antiparallel -pleated sheet
arrangement. The chains do not fold back on each other but are
in a fully extended conformation.
-Pleated Sheet
1- Polypeptide chains lie adjacent to one another;
may be parallel or antiparallel
2- R groups alternate, first above and then below
plane
3- Each peptide bond is trans and planar
4- C=O and N-H groups of each peptide bond are
perpendicular to axis of the sheet
5- C=O---H-N hydrogen bonds are between
adjacent chains and perpendicular to the
direction of the sheet
 Beta-Sheets

• Beta-sheets formed
from multiple side-by-
side beta-strands.
• Can be in parallel or
anti-parallel
configuration
• Anti-parallel beta-
sheets more stable
The arrangement of hydrogen bonds in (a) parallel

Fig. 4-4a, p.86

 pleated

antiparallel -pleated sheets.

Fig. 4-4b, p.86

 Beta-Sheets
• Side chains point alternately above and below the plane
of the beta-sheet
• 2- to 15 beta-strands/beta-sheet
• Each strand made of ~ 6 amino acids
The three-dimensional
form of the antiparallel
-pleated sheet
arrangement. The chains
do not fold back on each
other but are in a fully
extended conformation

Fig. 4-5, p.87

• Supersecondary Structures:
Combination of secondary structures of
the protein in many ways as the
polypeptide chain folds back on its self..
Schematic
diagrams of
supersecondary
structures

Fig. 4-8, p.88

Schematic diagrams of supersecondary structures. Arrows
indicate the directions of the polypeptide chains. (a) A unit 

Fig. 4-8a, p.88

an  unit

Fig. 4-8b, p.88

 Schematic diagrams of supersecondary structures.
Arrows indicate the directions of the polypeptide chains.
(c) a -meander

Fig. 4-8c, p.88

the Greek key

Fig. 4-8d, p.88

»Motifs:
Are supersecondary
structures, sometimes
called modules
.
(a) The
complement-
control protein
module.

Fig. 4-9a, p.89

(b) The immunoglobulin
module.

Fig. 4-9b, p.89

Forces that stabilize the tertiary structure of proteins
 Hydrogen
bond
Hydrophobic
interactions and
van der Waals
interactions
Disulfide
bridge
Ionic bond

Polypeptide
backbone
(a) A ribbon model (b) A space-filling model
Fibrous –
1) Polypeptides arranged in long strands or sheets
2) Water insoluble (lots of hydrophobic AA’s)
3) Strong but flexible.
4) Structural (keratin, collagen)

Globular –
5) Polypeptide chains folded into spherical or globular form
6) Water soluble
7) Contain several types of secondary structure
8) Diverse functions (enzymes, regulatory proteins)
A comparison of the shapes of fibrous and globular proteins:
(a) Schematic diagrams of a portion of a fibrous protein and of a globular protein.
(b) Computer-generated model of a globular protein. The color-coding in this model differs from
that of models of smaller molecules. The carbons are represented by light blue spheres, and
the yellow spheres represent sulfur.
Globular Proteins Have a Variety of Tertiary Structures
Each of these proteins has a distinct structure, adapted for its particular
biological function, but together they share several important properties
with myoglobin. Each is folded compactly, and in each case the hydrophobic
amino acid side chains are oriented toward the interior (away from water) and
the hydrophilic side chains are on the surface. The structures are also stabilized
by a multitude of hydrogen bonds and some ionic interactions.

The three-dimensional structure of a typical globular protein can be considered an

assemblage of polypeptide segments in the alpha -helical and beta -sheet
conformations, linked by connecting segments. The structure can then be defined by
how these segments stack on one another and how the segments that connect them
are arranged.

Two important terms that describe protein structural patterns or elements in a

polypeptide chain. The first term is motif, also called a supersecondary
structure or fold.
The first term is motif, also called a supersecondary structure or fold. A motif is simply a
recognizable folding pattern involving two or more elements of secondary structure and
the connection(s) between them. Although there is some confusing application of these
three terms in the literature, they are generally used interchangeably. A motif can be very
simple, such as two elements of secondary structure folded against each other, and
represent only a small part of a protein.
An example is in (Fig. 4–17a). A motif can also be a very elaborate structure involving
scores of protein segments folded together, such as the barrel (Fig. 4–17b). In some cases,
a single large motif may comprise the entire protein.

We have already encountered one well-studied motif, the coiled coil of

alpha-keratin, which is also found in some other proteins. Note that a motif is not a
hierarchical structural element falling between secondary and tertiary structure.
It is a folding pattern that can describe a small part of a protein or an entire
polypeptide chain.
The second term for describing structural patterns is domain. A
domain, as defined by Jane Richardson in 1981, is a part of a
polypeptide chain that is independently stable or could undergo
movements as a single entity with respect to the entire protein.
Polypeptides with more than a few hundred amino acid residues
often fold into two or more domains, sometimes with different
functions. In many cases, a domain from a large protein will retain its
native three-dimensional structure even when separated (for
example, by proteolytic cleavage) from the remainder of the
polypeptide chain. Different domains often have distinct functions,
such as the binding of small molecules or interaction with other
proteins. Small proteins usually have only one domain (the domain is
the protein)