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Energetics and kinetics of protein folding
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Comparison to other self-assembling systems?
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The search for the conformational energy minimum is global not
a combination of multiple independent local searches
Traveling salesman problem a classic exampleof a global search problem
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The conformationa
l energy landscape
describes the relative
energy of all possible
conformational states of a
moleculeTwo-dimensional energy landscape
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Frustrated systems
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Christian Anfinsen
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The thermodynamic hypothesis
The native structure of a protein is determinedsolely by the sequence of amino acids in itspoly-peptide chain and represents the state of the lowest conformational energy under nativeconditions.
QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Nobel Prize in Chemistry 1972
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Solving the energetic problem
Hydrophobic effectConformational entropy
Hydrogen bondsElectrostatic interactions
+ Van der Waals interactions
very small Number
Make more stabilizing interactions than you break
5-15 kcal
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5 hydrophilic0 hydrophobic
11 hydrophilic 4 hydrophobic
16 hydrophilic14 hydrophobic
With increasing size the ratio of surface to buried residues decreases
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Entropic cost per amino acid 0.6kcal/mol*ln10=1.3 kcal/mol
Average number of methyl groups per hydrophobic amino acid 5Hydrophobic effect per buried amino acid = 5*0.8 kcal/mol=4 kcal/mol
---> ~ 1/3 of amino acids need to be buried
V=4/3 r3
x=2 ; y=4 n= 64 ratio = 8x=3 ; y=5 n=125 ratio = 4.6x=4 ; y=6 n=216 ratio = 3.4
4/3 x3
4/3 y3
hydrophobic total=
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Using the hydrophobic effect to evade immuneDetection: Neisseria gonorrhoeae pilin
Parge et al. 1995 Nature
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Using the hydrophobic effect to evade immuneDetection: Neisseria gonorrhoeae pilin
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Levinthal’s paradox
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Proteins have an incredible number of possible conformational states, yet they are able to fold very quickly.
Cyrus Levinthal
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Number of particles in the universe ~1085
150 AA domain 10 different conformations per side chain-------> 10150 possible conformations.
Atomic vibrations occur on fsec. (10-15 sec) time scale
Time to search all possible conformations >> age of the universe
Levinthal’s paradox
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Levinthal’s paradox
There must be a code / mechanismThat allows proteins to fold within a reasonablePeriod of time.
Two models: Frame work
Global collapse
Random protein sequences typically do not fold, neither do most other polymers.
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Framework model
Secondary structure elements form firstPacking of secondary structure elements leads to molten globuleRepacking of the core in the molten globule leads to native structure
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Global collapse model
- Protein collapses due to hydrophobic effect- Hydrophobic environment drives formation of secondary structure to form molten globule- Repacking of molten globule leads to native structure
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Phi value analysis
Phi value =1 interaction already exists in transition statePhi value =0 interaction is not part of transition state
Alan Fersht
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Current state of debate
A detailed understanding of protein folding remains illusive because we still lack experimental information on many of the states along the folding trajectory
The transition state of a two-state folder tends to be very compact.
Proteins with similar folds tend to fold following a similar mechanism.