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Mm4mx MD Stote
Mm4mx MD Stote
Dynamics Simulations
Roland H. Stote
Institut de Chimie LC3-UMR 7177
Université Louis Pasteur
Strasbourg France
1EA5
Title Native Acetylcholinesterase (E.C. 3.1.1.7) From Torpedo Californica At 1.8A Resolution
Classification Cholinesterase
Compound Mol_Id: 1; Molecule: Acetylcholinesterase; Chain: A; Ec: 3.1.1.7
Exp. Method X-ray Diffraction
1
Macromolecules in motion
• Local motions
– (0.01 à 5 Å, 10-15 à 10-1 s)
– Atomic Fluctuations
– Sidechain motions
– Loop motions
• Rigid body motions
– (1 à 10 Å, 10-9 à 1 s)
– Helix motions
– Domain motions
– Subunit motions
• Large scale motions
– (> 5 Å, 10-7 à 104 s)
– helix-coil Transitions
– Dissociation/Association
– Folding and unfolding
• Biological function requires flexibility (dynamics)
Energy Minimization
"E a # b # "E b # c # "E c ### "E MIN $ 0 # fin
! c
2
Central idea of Molecular
Dynamics simulations
• Biological activity is the result of time dependent interactions
between molecules and these interactions occur at the
interfaces such as protein-protein, protein-NA, protein-ligand.
3
Molecular dynamics simulations
• Approximate the interactions in the system using simplified
models (fast calculations). Include in the model only those
features that are necessary to describe the system.
Classical Dynamics
• Newton’s Equations of motion
dvi d 2ri
Fi = mi ! ai = mi ! = m! 2
dt dt
Fi = !"i E
• Position, speed and acceleration are functions of time
ri(t); vi(t); ai(t)
• The force is related to the acceleration and, in turn, to the
potential energy
• Integration of the equations of motion => initial
structure : ri(t=0); initial distribution of velocities: vi(t=0)
4
Dynamics: calculating trajectories
dvi d 2ri
Fi = mi ! ai = mi ! = m! 2
dt dt
• Simple case where acceleration is constant
dv
a= v = at + v0
dt
Simple case:
motion of a particle in one dimension
dv
• Acceleration: a=
dt
• If a is constant a≠f(t)
v(t) = at + v0
• Speed:
dx(t)
v(t) =
• Position:
dt
5
Balistic trajectory
Initial conditions are
x(0) = z(0) = 0 Z
vx (0) = vo cos
vz (0) = vo sin
V0
In the x direction
ax = 0 X
vx (t) = vo cos
x(t) = vo cos t
Potential Energy
1 2 1 2
E(R) = ! Kb ( b " b0 ) + ! K# (# " # 0 ) + ! K$ (1 + cos(n$ " % ))
1, 2 pairs 2 angles 2 dihedrals
4 .( + 1 2 ( + 6 1 8
6 0 ' ' 3 q q 6
+ ! 54& ij 0** -- " ** -- 3 +
ij ij i j
9
i, j 6
7 0
/ ) rij , ) rij , 3
2 & Dr ij 6:
6
Numerical Integration
• Taylor series development
t2 t3
x(t) = x0 + v0 t + a0 + a 0 + O(t 4 )
'
2 3!
• If we know x at time t, after passage of a certain time, Δt, we
can find x(t+Δt)
1 dE(RN )
ai (t) = !
m dri (t)
• Potential Energy
1 2 1 2
E(RN ) = ! Kb (b " b0 ) + ! K# (# " # 0 ) + ! K$ (1 + cos(n$ " % ))
1,2 pairs 2 angles 2 dihedrals
4 .( ' + 12 ( ' + 6 1 q q 8
6 ij ij i j 6
+ ! 54& ij 0** -- " ** -- 3 + 9
0) rij , ) rij , 32 &Drij 6:
i, j 6
7 /
7
Principle of the trajectory
t0+4 Δt
t0+2Δt
t0+7Δt
t0+Δt
t0
Integration algorithms
8
Trajectory of a macromolecule
• Initial positions x0
PDB file
• Xray
• NMR
• Model
• Initial velocities v0
Coupled to the temperature 3 m v2
NkT = ! i i
2 i 2
• Acceleration
Calculated from the force, that is,
from the derivative of the potential
energy. 1 dE
a=!
m dr
9
Molecular Dynamics Simulation programs
AMBER
CHARMM
NAMD
POLY-MD
etc
http://www.pharmacy.umaryland.edu/faculty/amackere/research.html
10
Molecular Dynamics
Practical Aspects
0 *# & 1 2 # & 6 - 4
2 , " " / q q 2
7 14! ij ,%% (( ) %% (( / +
ij ij i j
5
i, j 2 $
+ ijr ' $ r ' . ! rij 2
3 ij 6
11
Nonbonded Energy Terms
Electrostatic Forces
r r
+ - + +
4 .( + 1 2 ( + 6 1 8
6 0 ' ' 3 q q 6
+ ! 54& ij 0** -- " ** -- 3 +
ij ij i j
9
i, j 6
7 r
0/) ij , r
) ij , 32 & Dr ij 6
:
Truncation
• Switch
Bring the potential to zero between
ron and roff. The potential is not
modified for r < ron and equals zero
for r > roff
• Shift
Modify the potential over the entire
range of distances in order to bring
the potential to zero for r > rcut
• Long-range electrostatic
interactions
Ewald summation
Multipole methods (Extended
electrostatics model)
12
Treatment of solvent
• Implicit: The macromolecule
interacts only with itself, but the
electrostatic interactions are
modified to account for the
solvent
qi q j
E elec (r ) = A
!r
Treatment of solvent
• Explicit representation
The macromolecule is surrounded by
solvent molecules (water, ions) with
which the macromolecule interacts.
Specific nonbond interactions are
calculated
0 *# & 1 2 # & 6 - 4
2 ,%
" ij ( %
" ij ( / qi q j 2
7 14! ij ,% ( ) % ( / +
r r r
5
i, j 2 +$ ' $ ' . 26
3 ij ij ij
13
Periodic boundary conditions
• For explicit representation of
solvent
• The boundaries of the
system must be represented
Boundary Conditions
14
Some properties that can be calculated from a
trajectory
• Average Energie moyenne
• Temperature Fators
• Radius of gyration
15
Steps of a molecular dynamics
simulation
An application of Molecular
Dynamics Simulations
16
Acetylcholinesterase
17
1EA5
Title Native Acetylcholinesterase (E.C. 3.1.1.7) From Torpedo Californica At 1.8A Resolution
Classification Cholinesterase
Compound Mol_Id: 1; Molecule: Acetylcholinesterase; Chain: A; Ec: 3.1.1.7
Exp. Method X-ray Diffraction
18
Access of
ligands to the
active site is
blocked -->
requires
fluctuations
19
Molecular Dynamics Simulation of
Acetylcholinesterase
20
Effect of the His44Ala mutation on the Nucleocapsid
protein from the HIV virus - NC(35-50)
Working at the interface of theory and experiment
21
Primary function of NC is to bind nucleic acids
The life cycle of the HIV-1 retrovirus and the multiple roles of the nucleocapsid protein
NC
NC
NC
NC
22
Structural determinants for the specificity of NC for DNA
The structure of the mutant His44Ala:NC(35-50):an NMR, MM and FL study
•Two-dimensional 1H NMR
E. Kellenberger and B. Kieffer, ESBS
•pH 6.5 at 274K
23
From NMR
From MD
angular S rmsd (Å)
1.2 0.8
0.7
1
0.6
0.8
0.5
0.6 0.4
0.3
Ensemble of structures from MD 0.4
0.2
0.2
0.1
0
35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
residue number
Free H
Complex H
24
Difference between calculated and experimental Δδ
Δ !" (ppm)
1
G35 C36 W37 K38 C39 G40 K41 E42 G43 A44 Q45 M46 K47 D48 C49 T50
0.5
-0.5
-1
-1.5
-2
25
Study of the DNA/NC complex. Free energy decomposition.
LYS 47
MET 46
TRP 37
Decomposition of the binding free energy by amino acid for the native protein
Amino acids that contribute significantly to DNA binding are those most affected by the
mutation
26
Conclusions
Since molecules are dynamic, experimental structures alone can not give the
entire picture.
Computational Chemistry
Grant, Guy H., Richards, W. Graham
http://www.ch.embnet.org/MD_tutorial/
27
Acknowledgements
• Hervé Muller
• Elyette Martin
28