Matière complexe etfrustration géométrique

Sadoc’s meetingHydrophobic compaction

and protein folding

Jacques Chomilier, Isabelle Callebaut,Jean-Paul Mornon, Alain Soyer,Mathieu Lonquety, Nicolas PrudhommeIMPMC

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

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

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°

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)

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

Mean First Neighbours during simulationMIR = Most Interacting Residues (Maxima): in thecore of the protein

Hydrophobic compaction and protein folding

MIR

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

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

Voronoï tesselation

Voronoï cell foreach amino acid

Hydrophobic compaction and protein folding

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

Hydrophobic compaction and protein folding

TEFModular conception of proteins (elementaryfolding units)

TEF = Tightened End FragmentsMean = 28 Amino Acids

Super SSR

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

All developments available on a server

Hydrophobic compaction and protein folding

RPBS

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