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CMSE SEMINAR. Protein Folding mechanisms By Sefer Baday. OUTLINE. Proteins Protein Folding Forces Driving Folding Energy landscape The folding mechanism models Conclusion. Some Facts about Proteins. Composed of amino acids. - PowerPoint PPT Presentation
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CMSE SEMINAR
Protein Folding mechanisms
By
Sefer Baday
OUTLINE
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
VHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
PRIMARY STRUCTURE (amino acid sequence)
QUATERNARY STRUCTURE (oligomers)
SECONDARY STRUCTURE (helices, strands)
TERTIARY STRUCTURE (fold)
What is Protein Folding ?
• 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
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
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
Interactions between atoms within the protein chain
Interactions between the protein and the solvent
Electrostatic Interactions
Interaction of charged side chain with the opposide charged side chain.
221
Dr
qqF
NH3+ O
CO
CH2
H2C C
O
O- NH3+
(CH2)4
Hydrogen Bonds
Noncovalent bond Energy:10-40 kJ/ mol Strength varies with angle of hydrogen bond
interaciton.
van der Waals forces
Between all atoms Approximately 1kj/mol
r
Van d
er
Waals
pote
nti
al
Van d
er
Waals
Forc
e
r0
r0Van der waals radii of common atoms (nm):
H 0.1 nm C 0.17 nmN 0.15 nmO 0.14 nmP 0.19 nmS 0.185 nm
Average Strength of Interactions
Bond Type kJ/mol
Covalent Bond 250
Electrostatic 5
van der Waals 5
Hydrogen bond 20
The Hydrophobic Interaction
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
The average separation in the sequence between residues that are in contact with each other in native structure
Phi Value Analysis
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
Local interactions are main determinants of protein structures
unfolded stateTransition state
native state
Hydrophobic Collapse
Hydrophobic core forms first.
unfolded state
collapsenative state
Hydrophobic Collapse
Formation of hydrophobic globule may hinder the reorganization of both side chains and whole protein
Nucleation Model Unites hydrophobic collapse and frame work
model
unfolded state
formation ofa nucleus
native state
Nucleation Model
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
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
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