Transcript Slide 1
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 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 ?
• 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 = 3 100 ~= 5x10 47 .
If 100 psec (10-10 sec) were required to convert from a conformation to another one, a random search of all conformations would require 5x10 47 x 10 -10 sec = 1.6 x 10 30 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.
F q 1 q 2 Dr 2 NH 3 + O O C CH 2 H 2 C C O O NH 3 + (CH 2 ) 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 0 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 r 0 r
Average Strength of Interactions Bond Type Covalent Bond Electrostatic van der Waals Hydrogen bond kJ/mol 250 5 5 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 state Transition state native state
Hydrophobic Collapse Hydrophobic core forms first.
unfolded state collapse native 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 of a 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