Input files and instructions to run the concerted alchemical simulations for the estimation of the hydration free energies of small to medium sized solute molecules in water droplets using OpenMM described in Alchemical Transformations for Concerted Hydration Free Energy Estimation with Explicit Solvation, currently in press on the Journal of Chemical Physics.
Sheenam Khuttan ssheenam@gradcenter.cuny.edu
Solmaz Azimi sazimi@gradcenter.cuny.edu
Joe Wu jwu1@gradcenter.cuny.edu
Emilio Gallicchio egallicchio@brooklyn.cuny.edu
The repository is maintained by the Gallicchio's laboratory at Department of Chemistry of Brooklyn College of CUNY (compmolbiophysbc.org). The work is supported in part from a grant from the National Science Foundation (CAREER 1750511).
The project walks you over the steps to setup and run alchemical absolute binding free energy calculations for a series of solute complexes with water droplet (TIP3P model) using the Single Decoupling (SDM) OpenMM's plugin.
We recommend installing OpenMM from source since most of the steps required are the same as for building the SDM-related plugins. However, binary installations of OpenMM should probably also work. Detailed building instructions for OpenMM are here. SDM requires an OpenCL platform with GPUs from NVIDIA (CUDA) or AMD, which we assume are in place. We developed a docker image with all of the tools to build OpenMM.
SDM uses Desmond DMS-formatted files. OpenMM includes a python library to load molecular files in DMS Desmond format; however, the version of the Desmond file reader required for SDM is not yet included in the latest OpenMM sources. To patch the 7.3.1 OpenMM installation above with the latest DMS file reader, do for example:
cd $HOME/devel
wget https://raw.githubusercontent.com/egallicc/openmm/master/wrappers/python/simtk/openmm/app/desmonddmsfile.py
cp desmonddmsfile.py $HOME/devel/openmm-7.3.1/wrappers/python/simtk/openmm/app/
Then rebuild OpenMM from the sources in $HOME/devel/openmm-7.3.1.
The sqlitebrowser application is very useful to inspect DMS files.
ASyncRE is a package written in python to perform replica exchange (RE) simulations in asynchronous mode across a set of GPUs. To install it into a conda environment, do:
conda install numpy configobj
cd $HOME/devel
git clone https://github.com/egallicc/async_re-openmm.git
cd async_re-openmm
python setup.py install
VMD is an indispensable tool for visualization and analysis of trajectories. Also, we use the catdcd tool distributed with VMD to parse and concatenate .dcd trajectory files. For this tutorial we will assume that VMD is installed in /usr/local.
Complex directories of water-droplet with solutes (ethanol, 1-naphthol, diphenyltoluene, and alanine dipeptide) with both linear and logistic potential settings are available in the repository. The files have been produced by setting up the simulation parameters for each complex, defining the alchemical schedule, and running the workflow for setting up the receptor, and then each complex in turn.
Go to the simulation directories of each complex and launch the ASyncRE simulations. For example, assuming ASyncRE is installed under $HOME/devel/async_re-openmm:
To run simulation of the ethanol solute with water droplet under linear alchemical schedule, go to directory EtOH-lin (-lin complex directories specify linear alchemical schedule, -log complex directories specify logistic alchemical schedule with softplus parameters.)
Set the nodefile to point to a set of GPUs on the local machine. For example:
locahost,0:0,1,OpenCL,,/tmp
locahost,0:1,1,OpenCL,,/tmp
locahost,0:2,1,OpenCL,,/tmp
locahost,0:3,1,OpenCL,,/tmp
for a compute server with 4 GPUs when the OpenCL platform is the first platform (0).
./runopenmm $HOME/devel/async_re-openmm/bedamtemptwd_async_re.py water-droplet-ethanol_asyncre.cntl
Adjust the settings in the runopenmm script to reflect your environment.
Each Replica Exchange (RE) simulation is set to run for 480 minutes (48 minutes each cycle x 10 cycles). You can change the duration of the simulation run by changing the WALL_TIME in the *_asyncre.cntl file present in each complex directory.
Monitor the progress of each ASyncRE simulation by inspecting the *_stat.txt file. For example:
cd $HOME/water-droplet/complexes/EtOH-lin
cat water-droplet-ethanol_stat.txt
Each replica runs in a separate subdirectory named r0, r1, etc. Each cycle generates .out, .dms, .log, .pdb, and .dcd files. For example the binding energy samples for the first cycle of replica 2 are stored in the file r2/water-droplet-ethanol_1.out . The .dms files are used to start the following cycle. The .pdb and .dcd files are used for trajectory visualization.
The ASyncRE process can be killed at any time with ^C and optionally restarted. However, replicas currently running on remote machines are likely to keep running and may have to be killed before ASyncRE can be restarted. To start from scratch (that is from the first cycle) remove all of the replicas directories by doing rm -r r? r??.
Once the simulation has started, replica directories pointing at each lambda value in the alchemical schedule are produced.
In each replica directory, a *.out is created, producing columns of values in the order: temperature, lambda, lambda1, lambda2, alpha, u0, w0, total potential energy, binding energy.
This output file can then be used to analyze the average value of different parameters over the course of simulation.
Additionally, to visualize the trajectories of the solute-complex binding, *.dcd files are produced which can be used along with the *.pdb file in the complex directory with VMD.
cd $HOME/water-droplet/complexes/EtOH-lin
vmd -f water-droplet-ethanol_6.pdb water-droplet-ethanol.dcd