ABFE

This package has been developed as a specific protocol for calculating ABFE, employing the double-system/single-box (DSSB) AbsoluteDG method for calculating absolute binding free energies through non-equilibrium switching. It involves two distinct simulations: the first focuses on the transition of a ligand from a bound state in the enzyme's active site to an unbound state within the simulation box. Conversely, the second simulation observes the ligand moving from an unbound state to a bound state within the active site. Throughout the calculations, the ligand is maintained in the active site using a system of restraints.

The package is based on tools implemented in pmx for the protocol of calculating absolute binding free energy and sire for calculating the correction introduced by restraints into the system.

In this protocol, all necessary tools are adapted to use a scheme of holding ligands using only pairwise distance restraints, rather than Boresh restraints, as was done in the basic approach.

For detailed technical information, you may refer to the ABFE_cli.py and ABFE_cli.sh scripts in ABFE/docker_build/abfe_pipeline directory for the main simulation launch protocol and calculation organization. In the same folder you can find AbsoluteDG_child.py for the pairwise distance restraints generation block, and StandardState.py for calculating the correction to the final free energy due to the error introduced by the presence of restraints in the system.

The package itself consists of files for assembling a Docker image ready for running simulations, as well as an example of execution.

Usage

First, download the repository.

git clone https://github.com/insilicomedicine/ABFE.git

Then, build the Docker image:

cd ./ABFE/docker_build
DOCKER_BUILDKIT=1 docker buildx build --progress=plain -t abfe:user .

After that, you can run the image:

docker run --name abfe -it -v /path/to/your/data:/home/jovyan/data abfe:user

Inside a container, you may need to change the ownership of the /home/jovyan/data directory.

cd /home/jovyan/data
sudo chown -R jovyan:users .

After finishing all your calculations, you will need to change the ownership back to work with the files outside of the container.

Example

You can find example data for processing in 'example' folder. Just copy both sub folders (pdbs and scripts) to path/to/your/data

#From root folder
cd ./ABFE/example
cp -r * path/to/your/data
cd path/to/your/data

Then run the script in scripts folder

cd ./scripts
bash run_bench.sh

Data

A list of 97 kinase complexes employed in the original research, along with their corresponding experimental energies, is available in data/kinase_systems.csv.

Additionally, Jupyter Notebook with example code for calculating the stability of ligand positioning during the equilibration phase can be found in data/Restraint_stability.ipynb.