SIMULATIONS DE REPLIEMENT DE CHAÎNES POLYPEPTIDIQUES

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Presentation transcript:

SIMULATIONS DE REPLIEMENT DE CHAÎNES POLYPEPTIDIQUES David PERAHIA1 Charles ROBERT1 Liliane MOUAWAD2 1 1 Laboratoire d’Ingénierie et de Modélisation Moléculaire 2 Institut Curie Université Paris-Sud 91405 Orsay

Primary structure 20 different types of amino acid residues aromatic side chains aliphatic side chains sulfur containing side chains aliphatic hydroxyl side chains basic side chains acidic side chains and their amide derivatives

Secondary structure a-helix b-strands

Different architectures Tertiary structure Different architectures a only b only Mixed a/b retinol-binding protein triosephosphate isomerase myoglobin Mixed a/b triosephosphate isomerase

Quaternary structure hemoglobin coat of poliovirus coat of poliovirus

Find the native structure from the sequence information Objectives: Find the native structure from the sequence information Find metastable structures Large scale exploration of the conformational space around the native structure Folding kinetics conformationel space extremely large Prerequisits: Simple model in order to perform very fast calculations Realistic force field 1 native structure should correspond to an energy minimum

ser ala thr tyr ala leu ile A SIMPLE MODEL 2 points per residue ser ala thr tyr ala leu ile Center of mass of side chains Ca-atoms

interactions between pseudo-atoms Cm Ca Cm Cm 4 Ca Ca 2 3 1 Ca Ca Cm Cm

Statistical force field 1 2 Ca Cm 3 Statistical force field 1230 PDB X-ray structures with sequence identity < 20%, and atomic resolution < 2 Å Ca1 - Cm2 Cm2 – Ca3 Ile Ile Histogram

Force Field w1 w2 w3 w4 w5 w6 w7 w8 w9 w10 w11

Molecular dynamics simulated annealing simulations 2000K linear conformations 800K 300K folded conformations

Contributions of Ca1- Ca4 and Cm- Cm interactions total total E(decoy)-E(X-ray) E(decoy)-E(X-ray) Ca1- Ca4 Ca1- Ca4 E(decoy)-E(X-ray) E(decoy)-E(X-ray) Cm- Cm Cm- Cm E(decoy)-E(X-ray) E(decoy)-E(X-ray) rmsd rmsd

ENERGY PARAMETER OPTIMIZATION ALGORITHM Assignment of parameters energy parameter set error rate function R0 Randomly pick a parameter Assign a random value to it new energy parameter set and error rate function R1 yes restore the previous parameters no if R1 < R0 or (mean of energy variations of decoys with respect to native energy) > 0 no evolution of R stop

Objectifs immédiats Optimiser les paramètres sur une grande variété de structures de protéines Recherche d’une fonction d’énergie optimale Recherche d’une stratégie de repliement optimale

native 4.17 Å 3.98 Å 4.60 Å