energetics and kinetics of protein folding
DESCRIPTION
Energetics and kinetics of protein folding. Comparison to other self-assembling systems?. The search for the conformational energy minimum is global not a combination of multiple independent local searches. Traveling salesman problem a classic example of a global search problem. - PowerPoint PPT PresentationTRANSCRIPT
Energetics and kinetics of protein folding
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Comparison to other self-assembling systems?
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
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
The conformationa
l energy landscape
describes the relative
energy of all possible
conformational states of a
moleculeTwo-dimensional energy landscape
Frustrated systems
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Christian Anfinsen
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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
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
5 hydrophilic0 hydrophobic
11 hydrophilic 4 hydrophobic
16 hydrophilic14 hydrophobic
With increasing size the ratio of surface to buried residues decreases
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=
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Using the hydrophobic effect to evade immuneDetection: Neisseria gonorrhoeae pilin
Parge et al. 1995 Nature
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Using the hydrophobic effect to evade immuneDetection: Neisseria gonorrhoeae pilin
Levinthal’s paradox
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Proteins have an incredible number of possible conformational states, yet they are able to fold very quickly.
Cyrus Levinthal
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
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.
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
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
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Phi value analysis
Phi value =1 interaction already exists in transition statePhi value =0 interaction is not part of transition state
Alan Fersht
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.