Molecular Dynamics SimulationsModeling Domain Movements of P-type ATPases

Pumpkin Annual Meeting

September 19, 2008

Outline

Setup

Model of the Molecular System

Energy Potential and Force Field

Choosing the Right Setup

Project Teasers

Model of the Molecular System Define the basic building blocks (The units)

Implicit or explicit water and lipid description

ε = 80

ε = 80

ε = 2

water

water

bilayer

Energy Potential

elecm n

mn

q qE

r

Non-bonding interactions

Describing the physics and chemistry of the interactions of the units

Bonding interactions

r or θ

E

EV

DW

rmn

Moving in Time

Collisions should occur smoothly!

Time step ~ 1/10 Tfast motion period

TC-H vib ~ 10 fs => Time step = 1 fs

Good

?

Bad

Input:

212

12

( .)i i

i i i

i i i

i i i i

t dE unit pos d t

t t m

t t t t t t t

t t t t t t t

F r

a F

r r v a

v v a a

ri(0) vi(0)

Output:trace of ri(t)

Bonding interactions Non-bonding interactions

The Cost Dependence on Unit Size

Small units Large units

Small mass/unit Large mass/unit

Fast motions Slower motions

Many units Few units

Small time steps Large time steps

Evaluation of force contribution - for every unit in every time step

Long simulations with few details

Short simulations with many details

handled in parallel on many computers

time steps cannot be handled in parallel on many computers

All-atom MD Lipid Study

P

P

P

To compare with: Single lipids observed with

X-ray Lipid headgroups seen in the

electron density map

POPC

Three Levels of MD

All atoms represented

Partial charges assigned to each atom.

Different types of each atom dependent on the surroundings.

Possible to describe specific chemistry.

Atoms collected in groups of app. 4 heavy atoms

Units have integral charges and descriptors for hydrophobicity, hydrogen-bond donor/acceptor and charge.

Atoms collected in domains and linkers

Surface chemistry described in equidistant points.

Charge and hydrophobicity represented.

Time scale: 100 ns Time scale: several μs Time scale: ms

Well established

Under development

Not developed

Development of Shape Model

Benefits

Keeps focus on large scale movements.

ms time scale for describing mechanism.

Explicit lipid bilayer.

Disadvantages

Only makes sense if surface chemistry and shape of domains are preserved throughout mechanism.

Detailed chemistry not described.

Implicit water.

Potentially difficult to describe single water, ATP, ions, ligands....

Are the Domains Preserved?A

M1M2M3M4

P N

M5M6

M7M10

6.66Å5.33Å4.00Å2.66Å1.33Å0.00Å

The People

Birgit SchiøttBiomodelling GroupDepartment of Chemistry

Maria MusgaardBiomodelling Group Department of Chemistry

Carsten WiufBiRCBioinformatics Research Center

Christian StormBiRC Bioinformatics Research Center

meBiRC

Bioinformatics Research Center