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6 Sampling Configuration Space
 

(Note: These tutorials are meant to provide illustrative examples of how to use the AMBER software suite to carry out simulations that can be run on a simple workstation in a reasonable period of time. They do not necessarily provide the optimal choice of parameters or methods for the particular application area.)
Copyright Ross Walker 2013

6.3 Using Accelerated Molecular Dynamics (aMD) to enhance sampling
Section 1

Formerly known as AMBER Advanced Tutorial 22

By Romelia Salomon, Levi Pierce & Ross Walker

1) Generating and Relaxing the Initial Structure

The first thing we need to do is generate an initial structure and relax this so that we can use it as the input for the molecular dynamics run itself. The pdb file for BPTI is included here 5PTI-DtoH-dry.pdb. We then use the program LEaP to generate the input files:

For this system we had to follow several steps to prepare the files.

  1. Modified the crystal structure file: Remove all water molecules.
  2. Form disulfide bridges and solvate the protein with TIP4P-Ew waters. The following lines show how this is done:

$AMBERHOME/bin/tleap
> source ~/amber11intel/dat/leap/cmd/leaprc.ff99SBi
> loadOff solvents.lib
> loadOff tip4pbox.off
> loadOff tip4pewbox.off
> $AMBERHOME/dat/leap/parm/frcmod.tip4pew
> HOH=TP4
> mol = loadpdb 5PTI-DtoH-dry.pdb
> bond mol.55.SG mol.5.SG
> bond mol.30.SG mol.51.SG
> bond mol.14.SG mol.38.SG
> addions2 mol Cl- 6
> solvatebox mol TIP4PEWBOX 10.5
> saveamberparm mol bpti-ff99SBi-large.prmtop bpti-ff99SBi-large.inpcrd
> quit

The protocol follows mimicked that of Shaw and coworkers. The water model used is TIP4P-Ew and the force field is ff99SB-I. For that, we additionally took the files generated in the previous step and selected only the The output files produced are: bpti-ff99SBi.prmtopp, bpti-ff99SBi.inpcrd.

After preparing the input files, we have to go ahead and minimize, heat and relax the system before performing the production run. We did this in stages:

  1. Minimize only the water, restraining the protein (20000 cycles)
  2. Let water move (NTP, 300K), restraining the protein
  3. Minimize water and protein (20000 cycles)
  4. Heat the system, restraining the protein (NVT 0 to 300K)
  5. Relax the system, restraining the protein heavy atoms (NPT, 300K, 0.5ns)
  6. Relax the system (NPT, 300K, 5ns)
min_wat.in heat-wat.in min-all.in
Minimize water
 System minimization:
&cntrl
   imin=1, ntmin=1, nmropt=0, drms=0.1
   maxcyc=2000, ncyc=1500, 
   ntx=1, irest=0,
   ntpr=100, ntwr=100, iwrap=0,
   ntf=1, ntb=1, cut=10.0, nsnb=20,
   igb=0,
   ibelly=0, ntr=1,
   restraintmask="!:WAT", restraint_wt=10.0,
&end
 /
Relax water
 LET WATER MOVE
&cntrl
  timlim = 999999., nmropt = 0,       imin = 0,
  ntx    = 1,       irest  = 0,       ntrx = 1,      ntxo   = 1,
  ntpr   = 500,     ntwx   = 500,     ntwv = 0,      ntwe   = 0,
  ntwr   = 5000,
  ntf    = 2,       ntb    = 2,
  cut    = 10.0,    nsnb   = 20,
  nstlim = 10000,   nscm   = 2500,   iwrap = 1,
  t      = 0.0,     dt     = 0.002,
  temp0  = 300.0,   tempi  = 200.0,    tautp=0.5,
  ntt    = 1, 
  ntp    =1 ,       taup = 1.0,
  ntc    = 2,       tol    = 0.00001,
  ibelly=0, ntr=1,
  restraintmask="!:WAT" , restraint_wt=10.0,
&end
 /
Minimize all atoms
  System minimization:
&cntrl
   imin=1, ntmin=1, nmropt=0, drms=0.1
   maxcyc=2000, ncyc=1500,
   ntx=1, irest=0,
   ntpr=100, ntwr=100, iwrap=0,
   ntf=1, ntb=1, cut=10.0, nsnb=20,
   igb=0,
   ibelly=0, ntr=0,
&end
 /
md-heat-300K.in md-dens-npt.in md-eq-npt-5ns.in
heat NPT 0.5ps
  Heating System
&cntrl
   imin=0, nmropt=1,
   ntx=1, irest=0,
   ntpr=500, ntwr=500, ntwx=500, iwrap=1,
   ntf=2, ntb=1, cut=10.0, nsnb=20,
   igb=0,
   ibelly=0, ntr=1,
   nstlim=250000, nscm=500, dt=0.002,
   ntt=1, temp0=0.0, tempi=0.0, tautp=0.5
   ntc=2,restraintmask=':1-58',
   restraint_wt=10.0,
&end

&wt type='REST', istep1=0, istep2=0, value1=1.0, value2=1.0, &end
&wt type='TEMP0', istep1=0, istep2=250000, value1=0.0, value2=300, &end
&wt type='END' &end
 /
equil NTP 0.5ns
 heat 
 &cntrl
  imin=0,irest=1,ntx=5,
  nstlim=250000,dt=0.002,
  ntc=2,ntf=2,
  cut=10.0, ntb=2, ntp=1, taup=1.0,
  ntpr=500, ntwx=500,
  ntt=3, gamma_ln=2.0,
  temp0=300.0,iwrap=1,
  ntr=1, restraintmask=':1-58',
  restraint_wt=10.0,
 /
 /
equil NPT 5ns
 equilibrate
 &cntrl
  imin=0,irest=1,ntx=5,
  nstlim=2500000,dt=0.002,
  ntc=2,ntf=2,ig=-1,
  cut=10.0, ntb=2, ntp=1, taup=2.0,
  ntpr=1000, ntwx=1000,
  ntt=3, gamma_ln=2.0,
  temp0=300.0,
 /
 /

We can now run these through pmemd. For example, running on one GPU on a regular desktop, storing results in 6 directories 1_, 2_, 3_ and so on:

$AMBERHOME/bin/pmemd.cuda -O -i min_wat.in -o min_wat.out -p ../*.prmtop -c ../*.inpcrd -r min_wat.rst -ref ../*.inpcrd

$AMBERHOME/bin/pmemd.cuda -O -i md_wat.in -o md_wat.out -p ../*.prmtop -c ../1_/*.rst -r md_wat.rst -ref ../1_/*.rst

$AMBERHOME/bin/pmemd.cuda -O -i min_sys.in -o sys_min.out -p ../*.prmtop -c ../2_/*.rst -r sys_min.rst -ref ../2_/*.rst

$AMBERHOME/bin/pmemd.cuda -O -i heat.in -o heat.out -p ../*.prmtop -c ../3_/*.rst -r heat.rst -ref ../3_/*.rst

$AMBERHOME/bin/pmemd.cuda -O -i density.in -o density.out -p ../*.prmtop -c ../4_/*.rst -r density.rst -ref ../4_/*.rst

$AMBERHOME/bin/pmemd.cuda -O -i eq.in -o eq.out -p ../*.prmtop -c ../5_/density.rst -r eq.rst

CLICK HERE TO GO TO SECTION 2


(Note: These tutorials are meant to provide illustrative examples of how to use the AMBER software suite to carry out simulations that can be run on a simple workstation in a reasonable period of time. They do not necessarily provide the optimal choice of parameters or methods for the particular application area.)
Copyright Ross Walker 2013