how to unboil an egg
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HOW TO UNBOIL AN EGG. SOME REFLECTIONS ON LIVING THINGS. Schroedinger:. Order requires large numbers of particles e.g. alignment of magnetic dipoles. Monod:. Monod: Specificity: Large number of weak interactions... Catalysis: ...that stabilize transition state. - PowerPoint PPT PresentationTRANSCRIPT
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HOW TO UNBOIL AN EGG
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..SOME REFLECTIONS ON LIVING THINGS.
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Schroedinger:
Order requires large numbers of particles e.g. alignment of magnetic dipoles.
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Monod:
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Monod:
Specificity: Large number of weak interactions... Catalysis: ...that stabilize transition state.
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...but how is the necessary three-dimensional structure created?????
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OPINIONS ON PROTEINFOLDING.
student postdoc
professor
Geneticist?
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“Denatured protein disordered, exposing parts that are otherwise on the inside...”
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Statistical Models of a Strongly Unfolded Protein
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Trichter
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Protein folding funnels
A lecture from Achim Besser
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Summary
• A small course through history
from Levinthal to pathways
• The old and the new view of protein folding
• The role of hydrophobic interaction during the folding process
• The structure of funnels
• The use of this knowledge for structure predictions (CGU)
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The beginning
• Experiments by Christian B. Anfinsen (1960‘s)
A protein can fold reversibly and the conformationof its native state is at the global minimum of its free energy
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The arising problemLevinthal‘s paradox
There are too many possible conformation so that it is impossible to find native state by random search.
conclusion
For each protein there has to be a specific sequence of conformational changes that brings the denatured protein to its native state the:
folding pathway
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vast conformational space
the golf-ball will "never" find its goal by random search
- 4 preferred phi-psiangels for each peptide bond - assuming 100 monomers
4100=1060 chain conformations
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folding pathway
well defined sequence of changes in conformation. The pathway leads the ball to its hole
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What causes the collapse
Hydrogen bonds aid collapse but otherwise play little role in dictating the specific architecture
Phi-psi-propensities predict only helices or strands but no collapse
Side-chain-centric view:
Backbone-centric view:
hydrophobic interactions are the strongest interactions among amino acids in water the collapse is dominated by hydrophobic interaction
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minimal model
hydrophilic hydrophobic
folding
sequence
But for detailed predictions for the native state all forces have to be considered
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Smooth funnel
a 100 residue chains4100 conformations
17100
104
ebut only are compact
),...,,( 21 nf free energy function
plot over all degrees of freedom is called energy landscape
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old and new viewsequential
micropath viewensemble view
principle
languagePaths, intermediates,
transition states, reaction coordinates
landscapes, funnels
explainswhat exponentials do
(what you see)
what molecules do
(how it works)
main problem search problem trap problem
proposed solution sequential pathways funnels
intermediates mileposts traps
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more realistic funnel
interaction in the folding process is about [kT]
Brownian motion causes large variations during the folding process
there is no specific pathway for
D N
no sequential but parallel events, folding is a diffusion like process
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D N
classical trajectories folding via multiples routes
D
N
D
N
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intermediate and transition state
D N
I
D I N
possible schemes
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uphill and downhill pathways
A: no favourable contacts are broken
B: favourable contacts are broken
made possible by thermal energyor
chaperonin proteins
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the bottom of the funnel
rugged: other conformations can be populated under native conditionsthis is important for protein function.
smooth: only small fluctuations around N are allowed
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Protein Folding
An Urgent Problem in the Post-Genomic Era
Protein EnergyLandscape
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Atomic-Detail Computer SimulationModel System
Molecular Mechanics Potential
ji ij
ji
ji ij
ij
ij
ijij
impropersdihedrals
N
n
n
anglesbondsb
Dr
rr
KnK
kbbkV
,,
612
20
1
20
20
4
cos1
Energy Surface Exploration by Simulation..
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Computing time versus molecular size – number of electrons CI/QMC-for correctly treating electron correlations very unfavourable scaling
Computing time versus molecular size – number of electrons CI/QMC-for correctly treating electron correlations very unfavourable scaling
2 x 1020 years
Ne2Ne
Number of Electrons (N)
3 Mio years
1 year
1 month12 hours
Size30 100 00010 0001 00010010
time ~ N6
bR
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Protein Folding
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Hydrophobic clusterTruncation
site
Active site
Staphylococcal Nuclease
Salt Bridge
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Protein Folding
Exploring the Folding Landscape
Future: - Short-Term: Understanding Rate Limiting Steps - Long-Term: Complete Folding Simulations?
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0 50 100 150 200 250 3000
5
10
15 C
Time (ps)
0
5
10
15 B
Dis
tan
ce (
Å) 0
5
10
15 A
Unmodified Charges
Charges Neutralized Here
Arg – Glu Salt Bridge
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- Free Energy Differences
(Thermodynamic Integration,e.g. drug design Umbrella Sampling e.g. conformational pathway).
3 4 5 6 7 8 9-1
0
1
2
3
4
5
6
7
Free
ene
rgy
(kca
l/mol
)
Distance CZ-CD (Å)
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IBM today will announce its intention to invest $100 million overthe next five years to build Blue Gene, a supercomputer that willbe 500 times faster than current supercomputing technology.Researchers plan to use the supercomputer to simulate thenatural biological process by which amino acids fold themselvesinto proteins. (New York Times 12/06/99)
IBM PLANS SUPERCOMPUTER THAT WORKS AT SPEED OF
LIFE
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Bundeshochleistungsrechner Hitachi SR8000-F1
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Science, 282, 440 (1998)34-residue villin headpiece subdomain
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Safety in Numbers
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“The grail had different manifestations throughout its long history, and many have claimed to possess it or its’ like” - J. Matthew, The Grail, Quest for the Eternal, (Thames and Hudson, London, 1981).