Download 1 Laboratoire d`Ingénierie et de Modélisation Moléculaire 2

SIMULATIONS DE REPLIEMENT DE CHAÎNES
POLYPEPTIDIQUES
David PERAHIA1
Charles ROBERT1
Liliane MOUAWAD2
1 Laboratoire d’Ingénierie et de Modélisation Moléculaire
2 Institut Curie
Université Paris-Sud
91405 Orsay
20 different types of amino acid residues
aliphatic side chains
sulfur containing side chains
basic side chains
aromatic side chains
aliphatic hydroxyl side chains
acidic side chains and their amide derivatives
Secondary structure
a-helix
b-strands
Tertiary structure
Different architectures
a only
myoglobin
b only
retinol-binding protein
Mixed a/b
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:
conformationel space extremely large
Simple model in order to perform very fast calculations
 Realistic force field
native structure should correspond to an energy minimum
A SIMPLE MODEL
2 points per residue
Center of mass
of side chains
ser
ala
thr
tyr
ala
leu
ile
Ca-atoms
interactions between pseudo-atoms
Cm
Ca
Cm
Cm
4
Ca
Ca
2
1
3
Ca
Ca
Cm
Cm
Statistical force field
Cm
2
1230 PDB X-ray structures with
sequence identity < 20%, and
atomic resolution < 2 Å
3
Ca
Ca
Cm2 – Ca3
Ca1 - Cm2
0.03
0.025
Ile
0.02
Histogram
Ca
1
Ile
0.025
0.02
0.015
0.015
0.01
0.01
0.005
0.005
0
0
-0.005
-0.005
3
4
5
rij
6
7
3
4
5
rij
6
7
Force Field
V  w1


i, j
bonds
 w3
1
kb rij - rij0
2


2
 h (ri , rj , r) L m,a ,a
i

 l (ri , rj , r)

L
L
m , ai , a j , C m i , C m
ai , a j , t i , t j
i, j
confinemen t interactions
between certain atoms
j
(rij )

L
m , a j ,Ca i ,C m
j
(rij )
j
 w6
m , ai ,Ca i ,C m i

L
m , ai , a j , C m i , C m
i, j
m
1-2 interactions
between Cm atoms

(rij )  w8
L
L
(rij )
m , ai , a j , C m i , C m
j
(rij )  w10
(rij )
m
m , ai , a j ,Ca i ,Ca
j
(rij )
i, j
m
1-4 interactions
between Cm atoms

C
(rij )  w4
m
i, j
m
interactions
between all Cm atoms
beyond 1-4
 w11
m , ai , a j ,Ca i ,Ca
i
intra -residue
Ca -Cm interaction
i, j
m
1-3 interactions
between Cm atoms
 w9 wai ,a j
j ,Ca i ,Ca j
m
i, j
adjacent-residues
Ca -Cm interactions
 w7
L
i, j
m
1-3 interactions
between Ca atoms
i, j
1-4 interactions
between Ca atoms
 w5

 w2
R
ai , a j , t i , t j
i, j
repulsive interactions
between all atoms
(rij )
j
(rij )
Molecular dynamics simulated annealing
simulations
2000K
linear conformations
800K
300K
folded
conformations
Contributions of Ca1- Ca4 and Cm- Cm interactions
1a32
1r69
E(decoy)-E(X-ray)
Cm- Cm
rmsd
E(decoy)-E(X-ray)
Ca1- Ca4
E(decoy)-E(X-ray)
E(decoy)-E(X-ray)
Ca1- Ca4
total
Cm- Cm
E(decoy)-E(X-ray)
E(decoy)-E(X-ray)
total
rmsd
ENERGY PARAMETER OPTIMIZATION ALGORITHM
Assignment of parameters
Randomly pick a parameter
Assign a random value to it
energy parameter set
error rate function R0
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
new energy parameter set
and error rate function R1
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
3.98 Å
4.17 Å
4.60 Å