M.

Prasad Naidu
MSc Medical Biochemistry,
Ph.D.Research Scholar

Our life is maintained by molecular
network systems
Molecular network
system in a cell
(From ExPASy Biochemical Pathways; http://www.expasy.org/cgi-bin/show_thumbnails.pl?2)
Proteins play key roles in a living
system
Three examples of protein functions
Catalysis:
Almost all chemical reactions in a
living cell are catalyzed by protein
enzymes.
Transport:
Some proteins transports various
substances, such as oxygen, ions, and
so on.
Information transfer:
For example, hormones.
Alcohol
dehydrogenase
oxidizes alcohols
to aldehydes or
ketones
Haemoglobin
carries oxygen
Insulin controls
the amount of
sugar in the
blood
Biology/Chemistry of Protein
Structure
Primary


Secondary


Tertiary


Quaternary
Assembly


Folding


Packing


Interaction
S

T

R

U

C

T

U

R

E

P

R

O

C

E

S

S

Primary structure
1.Primary structure denotes the number and sequence
of aminoacids in the peptide chain and location of
disulfide bonds,if present
2.The higher levels of organisation are decided by the
primary structure.
3.The primary structure is maintained by the covalent
peptide bond.
4.peptide bonds are not broken down by conditions
that denature proteins,such as heating or high
concentrations of urea.


5.Peptide bonds need prolonged exposure to a strong
acid or base at elevated temperatures to hydralyse non
enzymatically.
CHARECTERSTICS OF PEPTIDE
BOND
1.Partial double bond.It is rigid and planar.so there is
no freedom of rotation.
2.The C-N bond is trans in nature because of steric
interference of the R-groups when in the cis position.
3.the distance is 1.32A*which is midway between single
bond(1.49A*) and double bond (1.27 A*)
4.The side chains are free to rotate on either side of
peptide bond.
5.The angles of rotation known as Ramchandran
angles,determines the spatial orientation of peptide
chain.
NUMBERING OF AMINOACIDS
PSEUDOPEPTIDE;
Eg: Glutathione (gamma glutamyl-cysteinyl-glycine)
FORMATION OF PEPTIDE BOND;
Nameing of aminoacids in a polypeptidechain;
By changing the suffix in to yl
Eg; NH2-Gly-Ala-Val-COOH
glycyl-alanyl-valine
BRANCHED AND CIRCULAR
PROTEINS
Generally ,primary structure is linear.
Branched proteins are produced by interchain
disulfide bond
Eg:insulin



Circular protein: Eg; Gramicidin.
Clinical significance:
A single aminoacid change (mutation) in the linear
sequence may have profound biological effects on the
function.
Eg:
Sickle cell anemia:
HbS is produced by substitution of Valine in place of
Glutamic acid in the 6
th
position of beta chain of HbA.
Secondary structure
Secondary structure denotes the configurational
relationship between residues which are about 3-4
aminoacids apart in the linear sequence.

It is maintained by Hydrogen bonds,
Electrostatic bonds,
Hydrophobic bonds,
Van der waals forces.

1.Alpha helix
1.Alpha helix is a spiral structure.Polypeptide bonds
form the back-bone core and the side chains of
aminoacids extend outward to avoid interfering
sterically with each other.

2.It is the most common and stable conformation for a
polypeptide chain.
abundent in hemoglobin and myoglobin ----
globular and flexible molecule.
absent in chymotrypsin.
3.Present in keratins,fibrous proteins ------ major
component of hair and skin--- rigidity is determined
by number of disulfide bonds in it.
4.The structure is stabilized by hydrogen bonds
between NH and C=O groups of the main chain.

5.Each turn is formed by3.6 residues.the distance
between each aminoacid residue is 1.5 A*.

6.It is generally right handed because aminoacids
found in proteins are of L-variety,which exclude left
handedness.
Aminoacids that disrupts an alpha-helix;
1.Proline and Hydroxy proline will not allow the
formation of alpha-helix because
a) its secondary aminogroup is not geometrically
copatible with the right handed spiral of alpha-helix.
b)it inserts a kink in the chain,which interfers with
the smooth,helical structure.
2.Large number of charged aminoacids also disrupt by
forming ionic bonds or by electrostatically repelling each
other.
3.aminoacids with bulky side chains ,such as
tryptophan,valine,isoleucine,that branch at beta
carbon,if present in large numbers---- also interferes.
2.Beta pleated sheet:
1.the surfaces of beta-sheets appear pleated ----beta
pleated sheets.
2.it is formed by the polypeptide chain folding back on
itself.
3.The polypeptide chains are fully extended.The
distance between adjacent aminoacids is 3.5 A*.
4.It is stabilized by hydrogen bonds between NH and
C=O groups of neighboring polypeptide segments.
5.Strands run in same direction regard to the amino
and carboxy terminal ends of poly peptide chain--------
------- parallel.
Eg; Flavodoxin


6.Strands run in opposite direction ---------------
antiparallel
Eg; Silk fibroin
7.Both are present in Carbonic anhydrase.

3.Beta bends(reverse turns,Beta-turns):
1. are formed by the abrupt U-turn folding of
chain.Intrachain disulfide bridges stabilize these bends.
2.it reverse the direction of a polypeptide chain to form a
copact,globular shape.
3.they are usually present on the surface of protein
molecules.
4. it usually composed of 4 aminoacids,among one is
Proline -----causes kink
Glycine ----smallest


4.Non repetitive secondary structure:
1.small part of polypeptide chain forms loop or coil.
2. it is less regular structure than alpha helix and beta
pleated sheets.

5.SUPER SECONDARY STRUCTURE(MOTIFS):
Produced by packing side chains from adjascent
secondary structural elements close to each other.

Eg; Zinc finger motif common .found in transcription
factors.
COLLAGEN;
It is a triple helix.
Formed by mainly
Proline kinks because of its ring structure
Glycine- fits in to the restricted spaces where the three
chains of the helix come together.
3.TERTIARY STRUCTURE
1.Tertiary structure denotes three dimensional
structure of whole protein.
2.It defines steric relationship of aminoacids which are
far apart from each other in linear sequence,but are
close in three-dimensional aspect.
3.It is thermodynamically most stable.
4.it refers to folding of domains and to the final
arrangement of domains in the polypeptide.
4. It is maintained by Hydrogen bonds,
Electrostatic bonds,
Hydrophobic bonds,
Van der waals forces.
1.DOMAINS;
1.These are fundamental functional and three
dimensional structural units of polypeptides.
2.The core of domain is built from combinations of super
secondary structural elements (motifs).
5.Domain is a compact globular unit of protein.These
are connected with relatively flexible areas of protein.
Eg; Phenyl alanine hydroxylase enzyme contains 3
domains,one regulatory,one catalytic and one protein-
protein interaction domains.
2.Protein folding:
1.Interactions between the side chains of aminoacids
determine how a long polypeptide chain folds into
intricate three-dimensional shape of the
functionalprotein.
2.interactions involving hydrogen bonds,hydrophobic
bonds and disulfide bonds all exert an influence on the
folding process.
3.ROLE OF CHAPERONS IN PROTEIN FOLDING;

1.CHAPERONES are required for proper folding of
many species of proteins.
2.chaperones-also known as heat shockproteins-
interact with the polypeptide at various stages during
the folding process.
4.QUATERNARY STRUCTURE
1.It denotes polypeptide subunits aggregate to form
one functional unit. .
2.It is maintained by Hydrogen bonds,
Electrostatic bonds,
Hydrophobic bonds,
Van der waals forces.


3.Depending on the number of polypeptide
chains,protein is termed as
1.monomer,
2.dimer, Eg;creatine kinase
3.tetramer.
Eg;1.Hemoglobin,
2. Immunoglobulin.
PROTEIN MISFOLDING
1.protein folding is trail and error process that can
sometimes result in improperly folded molecules.
2.misfolded proteins are usually tagged and degraded
with in the cell.
3.if they accumulate causes diseases.
Eg;
1.Amyloidoses:
Seen in Alzeimers disease;
It is a neuro degenerative disease charecterised mainly
by cognitive impairment.
B.PRION DISEASE;
1.PRION PROTEIN IS A CAUSATIVE of transmissible
spongiform encephalopathies,
Creutzfeldt-jakob disease in humans,
Scrapie in sheep,
Bovine spongiform encephalopathy in cattle.
Summary
Proteins are key players in our living systems.
Proteins are polymers consisting of 20 kinds of amino
acids.
Each protein folds into a unique three-dimensional
structure defined by its amino acid sequence.
Protein structure has a hierarchical nature.
Protein structure is closely related to its function.
Protein structure prediction is a grand challenge of
computational biology.