Lecture 6
Molecules
of Life
Proteins-II
LIF111
The Central Dogma of Molecular Biology
YGGFL is a different polypeptide than LFGGY
Primary structure of proteins
Proteins can be broadly classified into two structural classes
Fibrous proteins Globular proteins
Polypeptide chains are organized as strands or sheets. In the case of globular proteins one or more polypeptide
Collectively many such molecules contribute towards the chains are folded in compact rounded shapes. Most
shape and internal organization of the cell. enzymes are globular proteins.
[Link] [Link]
-gallery/[Link] [Link]
[Link]
Collagen [Link]
com/Collagen+-+B-+rgam
ertiary+structure
How does a protein’s three-dimensional
structure emerge?
The primary structure of the protein gives rise to the protein’s shape in the
following ways:
1) It allows hydrogen bonds to form between the C=O and N-H groups of
different amino acids along the length of the polypeptide chain.
2) It puts “R” groups into positions that allow them to interact. Through their
interactions the chain is forced to bend and twist.
Peptide bond
The anatomy of the peptide backbone
The peptide bond is planar due to its partial double bond character
The peptide bond is essentially planar
Think of the polypeptide chain as a set of rigid playing cards joined by links that can swivel a bit. Each card is a
peptide group. Atoms on either side of it can rotate slightly around their covalent bonds and form bonds with
neighboring atoms.
Second level of protein structure
Hydrogen bonds form at short intervals along the new polypeptide chain and they give rise to a coiled or
extended pattern known as the secondary structure of the protein.
• Alpha helix
• Beta Sheets
Alpha helix (α helix)
Features:
1. It is a rod like structure.
2. Backbone is inside while side chains are
on the outside.
3. Hydrogen bonding between CO and NH
groups of the main chain stabilizes the
structure.
4. CO group of residue R hydrogen bonds
with the NH group of residue R+4.
5. Rise per residue is 1.5Å, residues per turn
is 3.6.
6. Most α-helices observed naturally are
right-handed helices.
α-helical
coiled coil
The helical content of a protein may vary anywhere between 0% to 100%.
75% of AAs in Ferritin, an iron storage protein is in alpha-helices.
α-helices are usually less than 45Å long. However, two or more α-helices can entwine to form a very stable structure, which can have a
length of 1000Å or more.
Such α-helical coiled coils are found in many structural proteins e.g. myosin, tropomyosin in muscle, Fibrin in blood, Keratin in hair etc.
Beta sheet (β sheet) Features:
1. Distance between two successive amino acids is
3.5Å.
2. The side chains are at 180° to each other.
3. Adjacent β-strands are linked by hydrogen
Anti-parallel β bonds.
sheet
4. In anti-parallel β-sheets the hydrogen bonds
between the CO and NH of adjacent strands
form between groups that are diametrically
opposite to each other.
5. In parallel β-sheets hydrogen bonds between
Parallel β sheet CO group of one amino acids forms with the NH
group of two amino acids downstream in the
other strand.
PINK: O
Blue: N 6. β-strands are depicted by arrows schematically.
White: H
Black: C
Many β-strands (4-10 or more) may come together in a protein. These β-strands may be all parallel to each other or anti-
parallel or mixed.
A and B are ball and stick and ribbon model of the same polypeptide, respectively. β-
strands may have twists. Side view of the schematic in B demonstrates the twists.
A protein rich in β-sheets, a fatty acid binding protein.
Question
A protein has 100 amino acids
Suppose each amino acid can take 2 conformations, each conformation takes 10-13sec
How much time does the protein take to try all conformations?
Conformations: 2100 = 1.26765E+30
Time to try all conformations = 1.26765E+17 sec
4019693684 years
= 4.1 * 109 years
~4000 million years
Protein Folding Problem
Proteins fold fast (0.1𝜇s - 1000s for some)
The Levinthal Paradox
At a meeting in Italy in 1968, Cyrus Levinthal raised the question of how, despite the huge number of
conformations accessible to it, a protein molecule can fold to its one precisely defined native structure so quickly
(microseconds, for some proteins).
How does the protein “know” what conformations not to search?
The folding process is directed in some way.
Dill. K.A and MacCallum. J.L., 2012, Science, 338. 1042-46.
Protein folding and Thermodynamics hypothesis
Anfinsen, 1962
• The native conformation is determined by the totality of interatomic interactions and
hence by the amino acid sequence, in a given environment.
• Native or natural conformation occurs because this particular shape is
thermodynamically the most stable in the intracellular environment. That is, it takes
this shape as a result of the constraints of the peptide bonds as modified by the other
chemical and physical properties of the amino acids.
How does a protein’s three-dimensional
structure emerge?
The primary structure of the protein gives rise to the protein’s shape in the
following ways:
1) It allows hydrogen bonds to form between the C=O and N-H groups of
different amino acids along the length of the polypeptide chain.
2) It puts “R” groups into positions that allow them to interact. Through their
interactions the chain is forced to bend and twist.
Questions
1. Which of the following is most important for specifying the 3D
shape of a protein?
[Link] peptide bond
[Link] amino acid sequence
[Link] with other polypeptides