Energetics and kinetics of protein folding

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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



The conformationa

l energy landscape

describes the relative

energy of all possible

conformational states of a

moleculeTwo-dimensional energy landscape

Frustrated systems



Christian Anfinsen



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=

Using the hydrophobic effect to evade immuneDetection: Neisseria gonorrhoeae pilin

Parge et al. 1995 Nature



Using the hydrophobic effect to evade immuneDetection: Neisseria gonorrhoeae pilin

Levinthal’s paradox



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



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



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.

Energetics and kinetics of protein folding

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