CMSE SEMINAR
Protein Folding mechanisms
By
Sefer Baday
OUTLINE
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Proteins
Protein Folding
Forces Driving Folding
Energy landscape
The folding mechanism models
Conclusion
Some Facts about Proteins
Composed of amino acids.
Each sequence fold in unique structure-native structure
Proteins are functional only in their native states
Folding is reversibe unfolding or re-folding is possible
Modest changes in the environment can cause structural
changes in the protein,thus affecting its function
Protein structure hierarchical levels
PRIMARY STRUCTURE (amino acid sequence)
SECONDARY STRUCTURE (helices, strands)
VHLTPEEKSAVTALWGKVNVDE
VGGEALGRLLVVYPWTQRFFE
SFGDLSTPDAVMGNPKVKAHG
KKVLGAFSDGLAHLDNLKGTFA
TLSELHCDKLHVDPENFRLLGN
VLVCVLAHHFGKEFTPPVQAAY
QKVVAGVANALAHKYH
QUATERNARY STRUCTURE (oligomers)
TERTIARY STRUCTURE (fold)
What is Protein Folding ?
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Protein folding is the process by which a protein
assumes its functional shape or conformation.
Random Coil
Native conformation
Why is the “Protein Folding” so important
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Most of the proteins should fold in order to function
Misfolding cause some diseases.
Cystic Fibrosis ,affects lungs and digestive system
and cause early death
Alzheimers’s and Parkinson's disease
It may help us to understand the structure of proteins
which has not been known
LEVINTHAL PARADOX
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Let have Protein composed of 100 amino acids.
Assume that each amino acid has only 3 possible
conformations.
Total number of conformations = 3100 ~= 5x1047 .
If 100 psec (10-10 sec) were required to convert from a
conformation to another one, a random search of all
conformations would require
5x1047 x 10-10 sec = 1.6 x 1030 years.
However, folding of proteins takes place in msec to sec
order.
Forces that stabilize protein structure
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Interactions between atoms within the protein
chain
Interactions between the protein and the
solvent
Electrostatic Interactions
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Interaction of charged side chain with the
opposide charged side chain.
q1q 2
F
Dr 2
O
+
NH3
-
O
H2C C
O
C CH2
O
+
NH3
(CH2)4
Hydrogen Bonds
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Noncovalent bond
Energy:10-40 kJ/ mol
Strength varies with angle of hydrogen bond
interaciton.
van der Waals forces
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Between all atoms
Approximately 1kj/mol
Van der Waals potential
Van der Waals Force
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Van der waals radii
of common atoms (nm):
H 0.1 nm
C 0.17 nm
N 0.15 nm
O 0.14 nm
P 0.19 nm
S 0.185 nm
r0
r0
r
Average Strength of Interactions
Bond Type
kJ/mol
Covalent Bond
250
Electrostatic
5
van der Waals
5
Hydrogen bond
20
The Hydrophobic Interaction
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Hydrophobic means afraid of water
Hydrophobic residues are buried in while
hyrophilic residues stay outside.
Hydrogen Bonds
The kinetic Theory of Protein Folding
 Folding proceeds through a definite series of
steps or a Pathway.
 A protein does not try out all possible
rotations of conformational angles, but only
enough to find the pathway.
Energy Landscape
Energy Landscape
Molten Globule
Contact Order
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The average separation
in the sequence
between residues that
are in contact with each
other in native structure
Phi Value Analysis
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Experimental method to study of the structure
of the transition state
Using mutations as a structural report
Phi=1, transition state has native like
structure
Phi=0, transition state has denatured like
structure
The Framework Model
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Local interactions are main determinants of
protein structures
native state
unfolded state
Transition state
Hydrophobic Collapse
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Hydrophobic core forms first.
collapse
unfolded state
native state
Hydrophobic Collapse
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Formation of hydrophobic globule may hinder
the reorganization of both side chains and
whole protein
Nucleation Model
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Unites hydrophobic collapse and frame work
model
unfolded state
formation of
a nucleus
native state
Nucleation Model
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Substantial expulsion of water from the burial
of non polar surfaces
Good correlation between decrease in
hyrodynamic volume and increase in
secondary structure
Unfolding simulation of Ci2
The folding Pathways of Barnase
Conclusions
Non local interactions( Hydrophobic effect and
van der waals ) are needed to bring protein
into a globular conformation.
Chemically specific interactions( hydrogen
bonds, electorstatic interactions) determine
the fine detail of the protein structure
Conclusions
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The folding process is hierarchical
Native topology affects the folding
mechanism.
Nucleation method explains folding
mechanism better than framework and
hydrophobic collapse methods.
THANK YOU 
QUESTIONS
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