1. 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

2. 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

3. Secondary structure
a-helix
b-strands

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

5. Quaternary structure
hemoglobin
coat of poliovirus
coat of poliovirus

6. 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

7. 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

8. interactions between pseudo-atomsCm Ca Cm Cm 4 Ca Ca 2 3 1 Ca Ca Cm Cm

9. Statistical force field1 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

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

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

12. 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

13. 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

14. 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

16. native
4.17 Å
3.98 Å
4.60 Å