CMSE SEMINAR

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CMSE SEMINAR

• Protein Folding mechanisms
• By
• Sefer Baday

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OUTLINE

• Proteins
• Protein Folding
• Forces Driving Folding
• Energy landscape
• The folding mechanism models
• Conclusion

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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

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Protein structure hierarchical levels
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What is Protein Folding ?

• Protein folding is the process by which a protein
  assumes its functional shape or conformation.

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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
• Alzheimerss and Parkinson's disease
• It may help us to understand the structure of
  proteins which has not been known

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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.

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Forces that stabilize protein structure

• Interactions between atoms within the protein
  chain
• Interactions between the protein and the solvent

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Electrostatic Interactions

• Interaction of charged side chain with the
  opposide charged side chain.

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Hydrogen Bonds

• Noncovalent bond
• Energy10-40 kJ/ mol
• Strength varies with angle of hydrogen bond
  interaciton.

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van der Waals forces

• Between all atoms
• Approximately 1kj/mol

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Average Strength of Interactions
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The Hydrophobic Interaction

• Hydrophobic means afraid of water
• Hydrophobic residues are buried in while
  hyrophilic residues stay outside.

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Hydrogen Bonds
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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.

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Energy Landscape
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Energy Landscape
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Molten Globule
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Contact Order

• The average separation in the sequence between
  residues that are in contact with each other in
  native structure

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Phi Value Analysis

• Experimental method to study of the structure of
  the transition state
• Using mutations as a structural report
• Phi1, transition state has native like structure
• Phi0, transition state has denatured like
  structure

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The Framework Model

• Local interactions are main determinants of
  protein structures

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Hydrophobic Collapse

• Hydrophobic core forms first.

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Hydrophobic Collapse

• Formation of hydrophobic globule may hinder the
  reorganization of both side chains and whole
  protein

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Nucleation Model

• Unites hydrophobic collapse and frame work model

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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

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Unfolding simulation of Ci2
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The folding Pathways of Barnase
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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

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Conclusions

• The folding process is hierarchical
• Native topology affects the folding mechanism.
• Nucleation method explains folding mechanism
  better than framework and hydrophobic collapse
  methods.

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THANK YOU ?

• QUESTIONS
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