1 laboratoire d ingénierie et de modélisation moléculaire 2 institut curie université paris-sud...
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1 Laboratoire d’Ingénierie et de Modélisation Moléculaire2 Institut Curie
Université Paris-Sud91405 Orsay
SIMULATIONS DE REPLIEMENT DE CHAÎNES POLYPEPTIDIQUES
David PERAHIA1
Charles ROBERT1
Liliane MOUAWAD2
20 different types of amino acid residues
aliphatic side chainsaromatic side chains
sulfur containing side chains aliphatic hydroxyl side chains
basic side chains acidic side chains and their amide derivatives
Secondary structurehelix
strands
Tertiary structureDifferent architectures
only only
myoglobin retinol-binding protein
Mixed triosephosphate isomerase
Quaternary structure
hemoglobin coat of poliovirus
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
Prerequisits:
Simple model in order to perform very fast calculations
Realistic force field
conformationel space extremely large
native structure should correspond to an energy minimum
A SIMPLE MODEL
2 points per residue
ser ala thr tyr ala leu ile
Center of massof side chains
Catoms
interactions between pseudo-atomsinteractions between pseudo-atoms
1
2
3
4
C
C
C
C
C
C
C
C
C
C
Statistical force fieldStatistical force field
-0.005
0
0.005
0.01
0.015
0.02
0.025
0.03
3 4 5 6 7
CC2 – C2 – C33
IleIle
ijr
-0.005
0
0.005
0.01
0.015
0.02
0.025
3 4 5 6 7
CC1 - C1 - C22
IleIle
ijr
His
togr
amH
isto
gram
1
2
C
C
C
C
31230 PDB X-ray structures with 1230 PDB X-ray structures with
sequence identity < 20%, and sequence identity < 20%, and atomic resolution < 2 Åatomic resolution < 2 Å
Force FieldForce Field
,,,
,,,
,,,,,
,
,,,,
,,,,
,,,,
,
,,,
,,,
,
,,,,
,,,,
,
20
)(
)( )(L
)(L )(L
)(L )(L )(
)(L )(L)(
)(L 2
1
atoms certain between nsinteractio tconfinemen
atoms all between nsinteractio repulsive
41- beyondatoms C all between nsinteractio
atoms C between nsinteractio 41-
atoms C between nsinteractio 31-
atoms C between nsinteractio 21-
nsinteractio C-C residues-adjacent
ninteractio C-Cresidue-intra
atoms C between nsinteractio 41-
atoms C between nsinteractio 31-bonds
ji,ijttaa
ji,ijttaa
ji, mijCCaamaa
ji mijCCaam
ji, mijCCaam
ji, mijCCaam
ji mijCCaml
i mijCCam
ji mijCCaamh
ji, mijCCaam
jiijijb
rC
rRrw
rr
rr
rr
rrrkV
jiji
jijijijiji
jijijiji
jijijij
iiijiji
jiji
r,r,r
r,r,r
ji
ji
w2w1
w3 w4
w5 w6
w7 w8
w9 w10
w11
Molecular dynamics simulated annealing Molecular dynamics simulated annealing simulationssimulations
20002000KK
300K300K
800K800K
folded conformationsfolded conformations
linear conformationslinear conformations
Contributions of CContributions of CCCand Cand C- C- Cinteractionsinteractions
1a32 1r69
rmsd rmsd
E(d
ecoy)-
E(X
-ray)
E(d
ecoy)-
E(X
-ray)
E(d
ecoy)-
E(X
-ray)
E(d
eco
y)-
E(X
-ray)
E(d
eco
y)-
E(X
-ray)
E(d
eco
y)-
E(X
-ray)
total total
CCCC CCCC
CC- C- C CC- C- C
ENERGY PARAMETER OPTIMIZATION ALGORITHM
energy parameter seterror rate function R0
Assignment of parameters
Randomly pick a parameterAssign a random value to it
new energy parameter setand error rate function R1
if R1 < R0
or(mean of energy variations of decoys
with respect to native energy) > 0
yesnorestore the previous
parameters
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