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Matière complexe et frustration géométrique Sadoc’s meeting · Matière complexe et...
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Matière complexe etfrustration géométrique
Sadoc’s meetingHydrophobic compaction
and protein folding
Jacques Chomilier, Isabelle Callebaut,Jean-Paul Mornon, Alain Soyer,Mathieu Lonquety, Nicolas PrudhommeIMPMC
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Question: How to go from the Sequence to the 3Dstructure? This is protein foldingParadigm of structural biology: structure gives function
Hydrophobic compaction and protein folding
Protein Structure
Secondary StructuresHélice α Brins β
Primary StructureSequence
.LAVSASDLL.
TertiaryStructure
Compact
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Prediction=problem of molecular conformationof amino acids
Energetic solution unrealistic (around 150amino acids)
Hydrophobic compaction and protein folding
Protein foldingGlobular Protein = Micelle(inside hydrophobic, outsidehydrophilic)
Compact (hydrogen bonds):necessity to curve thepolypeptide chain
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Discrete space: (2,1,0) lattice:Sadoc’s object?
Truc from Jean-François
Hydrophobic compaction and protein folding
Folding Simulation
3.8 Å
τ1.7 Å
24 first neighbours
7 τ values from 64°to 143°
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Amino acid displacements simulated by Monte Carlo
Hydrophobic compaction and protein folding
Folding Simulation
Energy = Potential of Mean Force to describeinteractions of amino acid pairs
Simulation stopped at first stages of folding : 106 MC steps
Some segments compact (proto fragments); other not(linkers)
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100 simulations (different initial conditions)
Fragment limits (in amino acids) are robust: search tolook if amino acids are always surrounded by others
Hydrophobic compaction and protein folding
Proto Fragments
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Mean First Neighbours during simulationMIR = Most Interacting Residues (Maxima): in thecore of the protein
Hydrophobic compaction and protein folding
MIR
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Hydrophobic compaction and protein folding
MIR & nucleus92% MIR = Hydrophobic AA
Highly conserved (compulsary for folding, not forfunction)= topohydrophobic
65 % MIR: topohydrophobic ±3AA
Multiple Alignement: 90% are TH
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Folding Nucleus= set of AA(hydrophobic) distributed overthe sequence, necessary toproduce the folding: hydrophobicglue
Hydrophobic compaction and protein folding
MIR & nucleus
Half the MIR correspond to nucleusMultiple structures to overcome thedegeneracy
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Voronoï tesselation
Voronoï cell foreach amino acid
Hydrophobic compaction and protein folding
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Hydrophobic compaction and protein folding
Voronoï tesselationNumber of Voronoïcells sharing a facewith another one(first neighbours in3D space)
Sequence separation between the two amino acids
28 Amino acids
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Hydrophobic compaction and protein folding
TEFModular conception of proteins (elementaryfolding units)
TEF = Tightened End FragmentsMean = 28 Amino Acids
Super SSR
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Compacity achieved by lattice simulation: Compactfragments correspond to Secondary Structures
Predict amino acids necessary for the fold (MIR)
These positions can be used as distance constraints forthe molecular modeling of domains
Among a large set of predicted structures, compacity isa very good criterium of selection (driving motor forprotein folding = hydrophobic core)
Hydrophobic compaction and protein folding
Conclusions
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All developments available on a server
Hydrophobic compaction and protein folding
RPBS
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Many thanks to Jean-François for:Being patient with dummiesReducing anxiousness of his colleagues
Last but not least: I am the only one whosaw him doing experiments!
Do not forget Guggenheim museum atBilbao, sculptures from Serra
Hydrophobic compaction and protein folding
Rock around Sadoc