Using Hamiltonian replica exchange with GROMACS

When patching GROMACS with PLUMED, it is also possible to perform Hamiltonian replica exchange with different topologies. Although this feature is provided together with PLUMED, it is actually a new feature for GROMACS itself that can be enabled using the -hrex flag of mdrun. This implementation is very close to the one used to produce the data in this paper [17]. In case you find it useful, please cite this paper.

Warning
This feature is currently used by several groups and should be robust enough. However, be sure that you understand its limitations and to perform all the tests discussed in this page before using it in production.

In this short tutorial you will learn how to do two things:

• Generate scaled topologies with plumed partial_tempering. This is actually not directly related to the -hrex flag.
• Run GROMACS with replica exchange and multiple topologies.

# Generate scaled topologies

Plumed comes with a partial_tempering command line tool that can be used to generate scaled topologies. Notice that you might want to generate these topologies by yourself. This step is totally independent from the use of the -hrex flag.

The partial_tempering tool can be invoked as follows:

  plumed partial_tempering scale < processed.top


where scale is the Hamiltonian scaling factor and processed.top is a post-processed topology file (i.e. produced with grompp -pp) where each "hot" atom has a "_" appended to the atom type, e.g. change this

     1         HC     1    ACE   HH31      1     0.1123      1.008   ; qtot 0.1123


to this:

     1         HC_    1    ACE   HH31      1     0.1123      1.008   ; qtot 0.1123


Notice that the section that should be edited is the [atoms] section for all the molecules that you wish to affect (typically only for the solute, but you may also want to change solvent parameters). If you select all the atoms of the solute, you will be able to prepare topologies such as those needed in a REST2 simulation [68].

Also remember to first produce the processed.top file with grompp -pp. Editing a normal topol.top file will not work, because it does not contain all the parameters. The processed.top file should not have any "#include" statement.

# produce a processed topology
grompp -pp
# choose the "hot" atoms
vi processed.top
# generate the actual topology
plumed partial_tempering $scale < processed.top > topol$i.top


Warnings:

• It's not very robust and there might be force-field dependent issues!
• It certainly does not work with charmm cmap

Suggested tests:

1. Compare partial_tempering with scale=1.0 to non-scaled force field. E.g.
grompp -o topol-unscaled.tpr
grompp -pp
vi processed.top # choose the "hot" atoms appending "_". You can choose whatever.
plumed partial_tempering 1.0 < processed.top > topol-scaled.top # scale with factor 1
grompp -p topol-scaled.top -o topol-scaled.tpr
# Then do a rerun on a trajectory
mdrun -s topol-unscaled.tpr -rerun rerun.trr
mdrun -s topol-scaled.tpr -rerun rerun.trr
# and compare the resuling energy files. they should be identical

2. Compare partial_tempering with scale=0.5 to non-scaled force field. Repeat the same procedure but using "plumed partial_tempering 0.5". Choose all the atoms in all the relevant [atoms] sections (e.g. solute, solvent and ions). In the two resulting energy files you should see: long range electrostatics, LJ, and dihedral energy is half in the scaled case all other terms (bonds/bends) are identical.

# Run GROMACS

If GROMACS has been patched with PLUMED it should accept the -hrex option in mdrun. Please double check this (mdrun -h should list this possibility). Notice that not all the versions of GROMACS allow this feature. First of all prepare separate topologies for each replicas using plumed partial_tempering tool as shown above (or using some other tool). Then run a normal replica exchange with gromacs adding the flag "-hrex" on the command line.

A complete run script could be adapted from the following

# five replicas
nrep=5
# "effective" temperature range
tmin=300
tmax=1000

# build geometric progression
list=$( awk -v n=$nrep \
-v tmin=$tmin \ -v tmax=$tmax \
'BEGIN{for(i=0;i<n;i++){
t=tmin*exp(i*log(tmax/tmin)/(n-1));
printf(t); if(i<n-1)printf(",");
}
}'
)

# clean directory
rm -fr \#*
rm -fr topol*

for((i=0;i<nrep;i++))
do

# choose lambda as T[0]/T[i]
# remember that high temperature is equivalent to low lambda
lambda=$(echo$list | awk 'BEGIN{FS=",";}{print $1/$'$((i+1))';}') # process topology # (if you are curious, try "diff topol0.top topol1.top" to see the changes) plumed partial_tempering$lambda < processed.top > topol$i.top # prepare tpr file # -maxwarn is often needed because box could be charged grompp_mpi_d -maxwarn 1 -o topol$i.tpr -f grompp$i.mdp -p topol$i.top
done
mpirun -np $nrep gmx_mpi mdrun_d -v -plumed plumed.dat -multi$nrep -replex 100 -nsteps 15000000 -hrex


Notice that total cell could be charged. This happens whenever the scaled portion of the system is not neutral. There should be no problem in this. When used with pbc, GROMACS will add a compensating background.

Suggested check:

• Try with several identical force fields (hardcode the same lambda for all replicas in the script above) and different seed/starting point. Acceptance should be 1.0

Notice that when you run with GPUs acceptance could be different from 1.0. The reason is that to compute the acceptance GROMACS is sending the coordinates to the neighboring replicas which then recompute energy. If all the tpr files are identical, one would expect energy to be identically to the originally computed one. However, calculations made with GPUs are typically not reproducible to machine precision. For a large system, even an error in the total energy for the last significant digit could be on the order of a kJ. This results in practice in a lower acceptance. The error induced on the final ensemble is expected to be very small.

Warnings:

• Topologies should have the same number of atoms, same masses and same constraint topology. Some of these differences (e.g. masses) are not explicitly checked and might lead to unnoticed errors in the final results.
• Choose neighbor list update (nstlist) that divides replex. Notice that running with GPUs GROMACS is going to change nstlist automatically, be sure that it still divides replex.
• Option -hrex requires also option -plumed. If you do not care about plumed, just provide an empty plumed.dat file.
• It should work correctly if replicas have different force-field, temperature, lambda, pressure, in any combination. However, not all these combinations have been tried in practice, so please first test the code on a system for which you know the result.