Tertiary Structure of Proteins

• Tertiary structure refers to the complete

three-dimensional structure of the
polypeptide units of a given protein.
• Secondary structures of proteins often
constitute distinct domains.
• Domain is the basic unit of structure and
function
• Tertiary structure describes the relationship of
different domains to one another within a
protein.
• OR the final arrangement of domains in a
polypeptide.
• The interactions of different domains is
governed by several forces:
• These include hydrogen bonding, hydrophobic
interactions, electrostatic interactions and van
der Waals forces.
• A- helix and B- sheet --- hydrogen bonding and this
eliminates the possibility of water to disrupt the
structure of proteins.
DOMAINS:
• Polypeptide chains more than 200 amino acids in
length generally consists of two or more domains.
• Core of the domain is built from motifs.
• Folding of the peptide chain within the domain usually
occurs independently of folding in other domains.
• So each domain has the characteristics of a small
compact globular protein. It is independent of other
domains.
 Forces Controlling tertiary Structure

Hydrogen Bonding:
• Polypeptides contain numerous proton donors
and acceptors both in their backbone and in
the R-groups of the amino acids.

• The environment in which proteins are found

also contains the H-bond donors and
acceptors of the water molecule.
• H-bonding, occurs not only within and
between polypeptide chains but with the
surrounding aqueous medium.
Hydrophobic Forces:
• Proteins are composed of amino acids that
contain either hydrophilic or hydrophobic R-
groups.
• It is the nature of the interaction of the
different R-groups with the aqueous
environment that plays the major role in
shaping protein structure.
• Like attract like
• Polar- dissolves in polar
• N-polar dissolves in n-polar
• The spontaneous folded state of globular
proteins is :
balance between the opposing energetics of
H-bonding between hydrophilic R-groups
and
the aqueous environment
and
the repulsion from the aqueous environment
by the hydrophobic R-groups.
• The hydrophobicity of certain amino acid R-
groups tends to drive them away from the
exterior of proteins and into the interior.
• This driving force restricts the available
conformations into which a protein may fold.
Electrostatic Forces:
• Electrostatic forces are mainly of three types;
– charge-charge,
– charge-dipole and
– dipole-dipole.
 Charge-charge interaction

• Typical charge-charge interactions that favor protein folding

are those between oppositely charged R-groups.
Charge-dipole interactions:
• This refers to the interaction of ionized R-groups of
amino acids with the dipole of the water molecule.
• The dipolar groups include main chain NH and CO
groups as well as the polar groups of Ser, Thr, Asn,
Gln, Tyr, and Trp side chains.
• They completely lack formal charges;
• As expected, the dipolar NH groups from both main
chains and side chains bind anions and negatively
charged molecules,
• whereas the CO groups from both sources bind
metallic cations and positively charged molecules.
• Hydroxyl side chains act in a bifunctional manner,
because the proton and oxygen can interact with
negative and positive charges, respectively.
Van der Waals Forces:
• There are both attractive and repulsive van
der Waals forces that control protein folding.
• Attractive van der Waals forces involve the
interactions among induced dipoles that arise
from fluctuations in the charge densities that
occur between adjacent uncharged non-
bonded atoms..
• Repulsive van der Waals forces involve the
interactions that occur when uncharged non-
bonded atoms come very close together.
• The repulsion is the result of the electron-
electron repulsion that occurs as two clouds of
electrons begin to overlap.
• Van der Waals forces are extremely weak,
relative to other forces,
• it is the huge number of such interactions that
occur in large protein molecules that make them
significant to the folding of proteins.
 Quaternary Structure

• Many proteins contain 2 or more different

polypeptide chains that are held in association
by the same non-covalent forces that stabilize
the tertiary structures of proteins.
• The arrangement of these polypeptide
subunits is called the quaternary structure of
proteins.
• Primary structure is the amino acid sequence.
• Secondary structure refers to the spatial arrangement of amino
acid residues that are nearby in the sequence. Some of these
arrangements are of a regular kind, giving rise to a periodic
structure. The a helix and b strand are elements of secondary
structure.
• Tertiary structure refers to the spatial arrangement of amino acid
residues that are far apart in the sequence and to the pattern of
disulfide bonds.
• We now turn to proteins containing more than one polypeptide
chain. Such proteins exhibit a fourth level of structural
organization. Each polypeptide chain in such a protein is called a
subunit.
• Quaternary structure refers to the spatial arrangement of
subunits and the nature of their interactions.
• Two subunits- dimeric. The simplest sort of quaternary structure
is a dimer, consisting of two identical subunits. This organization
is present in the DNA-binding protein Cro found in a bacterial
virus called l(Figure 3.48).
Figure 3.48. Quaternary Structure. The Cro protein of bacteriophage l is a dimer of
identical subunits.
• More complicated quaternary structures also are common.
More than one type of subunit can be present, often in
variable numbers.
• Three subunits- trimeric
• Proteins with multiple polypetide subunits are oligomeric
proteins. Oligomeric proteins can be composed of multiple
identical polypeptide chains or multiple distinct polypeptide
chains.
• Proteins with identical subunits are termed homo-oligomers.
Proteins containing several distinct polypeptide chains are
termed hetero-oligomers.
• For example, human hemoglobin, the oxygen-carrying protein
in blood, consists of two subunits of one type (designated a )
and two subunits of another type (designated b), as illustrated
in Figure (next slide). Hemoglobin is, therefore, a hetero-
oligomeric protein.
• Thus, the hemoglobin molecule exists as an a2 b2 tetramer.
Subtle changes in the arrangement of subunits within the
hemoglobin molecule allow it to carry oxygen from the lungs to
tissues with great efficiency.
Figure 3.49. The a 2 b 2 Tetramer of Human Hemoglobin. The
structure of the two identical a subunits (red) is similar to but not
identical with that of the two identical b subunits (yellow). The
molecule contains four heme groups (black with the iron atom
shown in purple).
Viruses make the most of a limited amount of genetic information by
forming coats that use the same kind of subunit repetitively in a symmetric
array.
The coat of rhinovirus, the virus that causes the common cold, includes 60
copies each of four subunits (Figure). The subunits come together to form a
nearly spherical shell that encloses the viral genome.
(A) A schematic view depicting the three types of subunits (shown in red,
blue, and green) visible from outside the virus.
(B) An electron micrograph showing rhinovirus particles.
 PROTEIN FOLDING
• Major Question: Precisely how is the one-
dimensional sequence of a protein
programmed to achieve a definitive three-
dimensional structure?
• The transition is from a random coil to a
unique structure.
• There are no definitive answers!
• There are, however, several important
considerations.
• Let us now examine how amino acids are grouped together in a
complete protein.
• X-ray crystallographic and nuclear magnetic resonance studies have
revealed the detailed three-dimensional structures of thousands of
proteins.
• We begin here with a preview of myoglobin, the first protein to be seen
in atomic detail.
• Myoglobin, the oxygen carrier in muscle, is a single polypeptide chain of
153 amino acids.
• The capacity of myoglobin to bind oxygen depends on the presence of
heme, a nonpolypeptide prosthetic (helper) group consisting of
protoporphyrin IX and a central iron atom.
• Myo-globin is an extremely compact molecule.
• About 70% of the main chain is folded into eight a helices, and much of
the rest of the chain forms turns and loops between helices.
• The folding of the main chain of myoglobin, like that of most other
proteins, is complex and devoid of symmetry.
 • A unifying principle emerges from the distribution of side chains.
• The striking fact is that the interior consists almost entirely of nonpolar residue such
as leucine, valine, methionine, and phenylalanine.
• Charged residues such as aspartate, glutamate, lysine, and arginine are absent from
the inside of myoglobin.
• The only polar residues inside are two histidine residues, which play critical roles in
binding iron and oxygen.
• The outside of myoglobin, on the other hand, consists of both polar and nonpolar
residues.
• The spacefilling model shows that there is very little empty space inside

hydrophobic amino acids: yellow,

charged amino acids shown in blue
others shown in white

A space-filling model of myoglobin. A)The surface of the molecule has many charged amino
acids, as well as some hydrophobic amino acids. (B) A cross-sectional view shows that mostly
hydrophobic amino acids are found on the inside of the structure, whereas the charged amino
acids are found on the protein